Therapies for rare diseases: therapeutic modalities, progress and challenges ahead


Most rare diseases still lack approved treatments despite major advances in research providing the tools to understand their molecular basis, as well as legislation providing regulatory and economic incentives to catalyse the development of specific therapies. Addressing this translational gap is a multifaceted challenge, for which a key aspect is the selection of the optimal therapeutic modality for translating advances in rare disease knowledge into potential medicines, known as orphan drugs. With this in mind, we discuss here the technological basis and rare disease applicability of the main therapeutic modalities, including small molecules, monoclonal antibodies, protein replacement therapies, oligonucleotides and gene and cell therapies, as well as drug repurposing. For each modality, we consider its strengths and limitations as a platform for rare disease therapy development and describe clinical progress so far in developing drugs based on it. We also discuss selected overarching topics in the development of therapies for rare diseases, such as approval statistics, engagement of patients in the process, regulatory pathways and digital tools.


Although rare diseases affect small numbers of patients by definition (Box 1), they are estimated to collectively affect ~350 million patients globally1, more than double the number of patients affected by AIDS and cancer combined. While there have been substantial efforts to promote the development of therapies for rare diseases in the past few decades, supported by regulatory and economic incentives2, most of the estimated ~7,000 rare diseases still lack specific treatments. Moreover, recent analysis indicates that the number of rare diseases could be substantially higher than 7,000 (Box 1).

The vast majority of rare diseases are characterized by Mendelian inheritance, and the recent evolution and broader application of sequencing technologies have revealed the causes of novel rare diseases and have identified new mutations responsible for previously defined disorders3. In addition, emerging applications of advanced analytics such as facial recognition have the potential to improve the screening and diagnosis of some disorders4. Nevertheless, the rate of translation of knowledge of rare diseases into therapies lags far behind the rate at which this knowledge is being generated (Fig. 1).

Fig. 1: Indication of the gap between science and translation into therapies for rare diseases.

The graph shows the total number of publications per year extracted from PubMed using all rare disease names (leaf terms as well as higher-level terms) available from the analysis described in ref.153 and the number of orphan drugs receiving approval by the FDA (from 1987 to 2018) and the European Medicines Agency (EMA) (from 2000 to 2018) on a logarithmic scale. The number of approvals each year is indicated in the circles. The graph includes approved oncology orphan drugs.

With this lag in mind, the aim of this article is to outline the major therapeutic modalities5,6 available to researchers interested in translating advances in the scientific understanding of rare diseases into therapeutic interventions. Industry has traditionally focused on small‐molecule drugs, but advances in molecular biology and understanding of the human genome have enlarged the drug discovery toolbox, first to protein‐based therapeutics (proteins, peptides and antibodies) and more recently to antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs) and gene and cell therapies. These therapeutic modalities differ in their ability to target molecular disease mechanisms and/or to effectively reach certain cellular compartments (Fig. 2). Protein‐based therapeutics have enabled the modulation of extracellular targets and the replacement of dysfunctional circulating proteins, whereas ASOs, siRNAs and gene and cell therapy have widened the druggable target space to include targets and mechanisms that are difficult to address with small molecules and proteins, such as transcription factor targets and compensation for dysfunctional intracellular proteins. Together, these therapeutic modalities allow a broad coverage of targets and mechanisms, which can be expanded by combining modalities, such as small-molecule conjugation with an antibody.

Fig. 2: Therapeutic modalities: characteristics and regulatory approval data.

a | A comparison of selected general characteristics of the main therapeutic modalities discussed in this article, including their applicability based on the cause of disease at the protein level, the targeted step in the information flow from DNA to RNA to protein, the ultimate localization of the protein target and the delivery routes that are currently well-established. For modalities other than small molecules, other delivery routes are being investigated but therapies have not yet received regulatory approval, for example, oral administration of oligonucleotides and of proteins180. The tissues in which the target is expressed may also be relevant for some modalities; for example, adeno-associated virus vectors can be modified to selectively infect cells in particular tissues119. The asterisk indicates that the characteristics shown for cell and gene therapies do not apply to all cell therapies, which are highly diverse. b | Approvals of drugs for rare diseases by the FDA and the European Medicines Agency (EMA). The approval numbers for the FDA and the EMA are up to the end of 2018. For comparability with the FDA data, the total number of drugs approved as orphan drugs from 2000 to the end of 2018 are used for the EMA data, meaning that the number 187 includes products which have been withdrawn by the sponsor or for which the market exclusivity expired, and also extensions of indications (n = 23). At the end of 2018, there were 112 active market authorizations for orphan medicinal products in the European Union, not including 15 active extensions of the indication. However, the FDA and the EMA do not necessarily classify products in the same way, which may limit comparisons of these data. The ‘others’ category includes protein replacement therapies, enzymes, cytokines, blood, hormones/growth factors and vaccines.

Here, we present each modality with its respective strengths and limitations, as well as its clinical success specifically in rare diseases, and also discuss selected overarching topics in the development of therapies for rare diseases, such as the value of engaging patients in the process. Overall, we hope that this article may serve as a drug discovery introduction for the rare disease community and facilitate the translation of scientific advances into novel therapies.

Small molecules

Small molecules are the most well-established drug platform for diseases in general and continue to be attractive as therapeutic agents because of their multiple routes of administration, controlled dosing, stability, scale of synthesis and generally low cost of goods. Although concerns have been raised7 for many years that the rate at which small-molecule drugs reach the clinic is slowing, new screening technologies and advances in synthetic chemistry, computational screening and structural biology are enabling the discovery and design of novel bioactive molecules. There is also huge potential to expand the knowledge of previously understudied genes as drug targets, given that less than 700 of an estimated 3,000 disease-associated proteins encoded in the human genome are targeted by currently approved drugs8,9. Furthermore, even if a mutated-gene product may not be a druggable target, analysis of the associated pathway may identify a suitable target for small-molecule intervention.

Technology summary

The identification of small-molecule drug candidates generally depends on the screening of cell lines with libraries that typically range in size from ~103 to ~106 compounds. This approach has been boosted in the past two decades by the introduction of more efficient screening technologies and developments with chemical libraries to increase hit rates and quality10. An example is the filtering of chemical libraries to remove structures that may be more likely to have poor pharmaceutical properties (for example, based on Lipinski’s rule of five)11 and structures that are likely to be false positives owing to assay interference, although this approach is not without controversy12,13. Medicinal chemists then investigate derivatives of promising hits to optimize the effects in disease models, as well as their absorption, distribution, metabolism, excretion and toxicology (ADMET) characteristics, before selecting a candidate to carry forward into clinical testing.

The ability to set up a high-throughput screen where the readout relates directly to human physiology has been one of the limitations in translating small-molecule candidates from such screens into therapies for use in the clinic14. Importantly, however, for rare diseases, the molecular cause is often well characterized, in contrast to more common diseases. Furthermore, several recent developments, including induced pluripotent stem (iPS) cells, technologies for gene editing such as CRISPR–Cas systems15 and organoids16 have made possible the development of cellular disease models that are anticipated to have a strong translational relevance, as well as provide much higher throughput than possible previously.

Theoretically, iPS cells can be established from a patient’s skin biopsy sample and differentiated into the cell type of interest expressing the phenotypic characteristic of the disorder17. One of the first high-throughput screens using iPS cells derived them from the fibroblasts of a patient with spinal muscular atrophy (SMA) and differentiated them into motor neurons18. These cells demonstrated the characteristic disease features: notably, a decreased ability to differentiate into neurons. Screens using such cells have led to drug candidates, including the phase II SMA therapy LMI70, a small molecule that boosts production of a protein known as survival motor neuron protein (SMN) by binding to a complex of the SMN2 pre-mRNA and the cellular splicing machinery19. Three-dimensional organoid cultures provide an even closer mimic of tissue organization and functionality, making them an excellent model for screening for small-molecule drugs, particularly when drugs targeted at particular mutations are required20. The best application of this technology thus far is the modelling of mutations in the cystic fibrosis gene CFTR, as described in the next subsection.

Screens in model organisms including Saccharomyces cerevisiae (yeast), Caenorhabditis elegans (nematode), Drosophila melanogaster (fruit fly) and Danio rerio (zebrafish) are also emerging as important genetic and chemical discovery platforms, particularly for small-molecule drugs that may modify a disease phenotype21. These screens also take into account drug uptake into cells and toxicity considerations. The genomes of all these organisms have been sequenced, and they can be used in modifier screens for the identification of drug targets. The advent of CRISPR–Cas9-based genome editing and transgenic technology allows the introduction of specific human mutations. Simultaneous validation across several model organisms could accelerate the movement of potential therapies towards the clinic.

Clinical success and approvals

The success of small molecules in therapy for rare diseases has been driven by targeted screens and better disease modelling. For example, for cystic fibrosis, therapeutic small molecules have been derived from cell screens defined by knowledge of the underlying mutations in the CFTR gene, which lead to defects in protein production, trafficking, function, misfolding or premature degradation. In vitro screens led to the identification of the CFTR potentiator ivacaftor22,23, which was initially approved to treat 10 different mutations in patients with cystic fibrosis, with approval subsequently expanded to an additional 23 mutations24; further studies have indicated that it could be applicable to many more21. An assay for the correction of the folding and processing of CFTR allowed the development of lumacaftor, a compound that promotes CFTR trafficking, for use in combination with ivacaftor for patients with cystic fibrosis with the most common F508del mutation22. Recently, a three-drug combination for patients with one or two F508del alleles (representing ~90% of patients) demonstrated efficacy in phase III trials25 and has received FDA approval26. None of these combination treatments is a cure, but by targeting different phenotypic outcomes of a given mutation, it is possible to achieve significant clinical benefit. It is also noteworthy that in vitro assays, such as those based on cystic fibrosis intestinal organoids27, can indicate whether particular combinations of drugs that address different defects in CFTR function are likely to be effective in particular groups of patients. On the basis of the results of such assays and the drug safety profile, the FDA staff have worked with patients, advocacy groups, industry and academia to allow the use of approved drugs in additional patient populations with CFTR mutations that are too small for traditional clinical trials28, an approach that may also be relevant for other drugs targeting specific mutations in the future.

Small molecules can potentially target all tissues, although tissue exposure depends on the chemical structure. Lysosomal storage disorders (LSDs), many of which are caused by defects in lysosomal enzymes, are a good example of a set of rare diseases where this could be an advantage29. As discussed later, enzyme replacement therapy (ERT) is a well-established effective platform for some groups of patients with LSDs, but is costly to manufacture, requires injection and can be limited by the lack of penetrance of the enzyme to key pathological sites, such as the central nervous system (CNS). Two small-molecule LSD therapies that inhibit the biosynthesis of the substrates of defective enzymes (miglustat and eliglustat for Gaucher disease) and one that acts as a chaperone to stabilize and restore function to a mutant enzyme (migalastat for Fabry disease) are already approved, with further candidates in clinical trials, including the CNS-penetrant compound ibiglustat for Fabry disease.

Small molecules that promote stop codon readthrough are promising for drug discovery for rare diseases caused by such mutations in a particular gene30. For example, ~13% of patients with the muscle-wasting disease Duchenne muscular dystrophy (DMD) have stop codon mutations in the gene coding for dystrophin31, and a small molecule, ataluren, that promotes stop codon readthrough demonstrated efficacy in the mdx mouse model of DMD32. However, translation into patients has been difficult because of the low levels of readthrough, and ataluren is currently approved in the European Union but not in the United States.

Small-molecule drugs can also be used to increase the levels of proteins that can compensate for a lack of a protein product. For example, increased expression of the dystrophin-related protein utrophin has been shown to prevent pathology in the mdx model of DMD33, although small molecules which increase utrophin levels have not yet been successful in clinical trials. In DMD, several small molecules that address downstream effects such as inflammation and fibrosis are also showing efficacy in the clinic and can be used in combination31. Finally, small-molecule proteostasis modifiers, which increase the endogenous cellular response to stress and upregulate the chaperone heat shock protein 70 to promote protein folding, are being developed for LSDs29.

Strengths and limitations as a platform for rare disease therapies

Small molecules remain at the forefront of drug discovery because they can target many tissues, they can be produced at reasonable costs and their manufacturing is scalable. For rare diseases, if the causative molecular target is in a class with established tractability for small molecules, such as G-protein-coupled receptors or kinases, the vast scientific, clinical and regulatory experience with this platform can also be an advantage compared with emerging platforms discussed elsewhere in this article. Furthermore, the potential for phenotypic screening to identify molecules that have the desired therapeutic effect through unknown novel mechanisms could also be an advantage for rare diseases for which the molecular cause is unclear or multifactorial.

The major challenge is to find the right molecule that displays an excellent pharmacological effect and excellent pharmacokinetics but with few off-target effects, which sometimes requires extensive optimization of a lead candidate. The other main hurdles are access to sufficient numbers of chemical entities (outside biopharma companies) and the development of screens which are relevant to the disease state in vivo. There has been substantial progress in tackling both of these challenges in recent years; for example, through initiatives such as the European Lead Factory to enable academic researchers and small and medium-sized enterprises to screen novel targets with large pharma-quality compound libraries (see Related links). Furthermore, as screening for disease phenotypes improves, many of the drugs already shown to be safe and well tolerated in one condition may be repurposed to treat a (different) rare disease where there might be a common pathway for intervention, as discussed later in this article. Finally, as understanding of rare disease mechanisms improves, combination therapy targeting different aspects of disease pathogenesis, a common scenario in cancer, may become possible.

Antibody therapies

The first therapeutic monoclonal antibody (mAb), muronomab-CD3, was approved in 1986 for the treatment of organ allograft rejection34. Since then, this class of products has steadily grown such that therapeutic mAbs (and antibody-related products such as Fc-fusion proteins, antibody fragments and antibody–drug conjugates (ADCs))35 have become a dominant product class for the treatment of a variety of diseases, particularly cancers and immune disorders36. Antibodies exert their effect by modulating signalling pathways, recruiting cells or proteins to specific sites, delivering cytotoxins or neutralizing or modulating circulating factors.

Technology summary

mAbs are naturally produced by B lymphocytes, recognizing foreign antigens during the humoral immune response. The two key characteristics of a mAb are its specificity for a particular antigen and that this specificity is continuous. Efforts to exploit these features therapeutically date back to the 1970s37,38. However, the first murine mAbs had immunogenicity and a short half-life, and scientists realized that mouse/human chimeric mAbs, humanized mouse mAbs or human mAbs would be necessary for the development of effective mAb therapeutics. Four main approaches have since been developed to identify and produce such mAbs: phage display39, transgenic animals40, B cell immortalization and single B cell sorting41.

Antibody engineering is now well established, and antibodies can be produced as full-length naked mAbs or as smaller engineered antigen-binding fragments (Fab)42, providing desirable characteristics for specialized applications (for example, reaching higher concentration in confined settings such as the back of the eye) and characterized by a faster clearance, resulting in reduced systemic bioavailability and consequent reduced toxicity. Engineering techniques also allow the production of bispecific antibodies (BsAbs)43, which may have advantages over monospecific antibodies, such as the ability to direct effectors of the immune system to target tumour cells or to block two different targets simultaneously43,44. BsAb development is less straightforward than mAb development, however, with challenges including stability of the molecules, manufacturing and more complex toxicology assessments. Although multiple BsAb formats have been developed and more than 50 BsAbs have entered clinical trials, so far only two BsAbs have reached the market.

The antibody constant region (Fc) can also be fused to another non-antibody-related protein domain and used as a standalone therapeutic or the full-length antibody can be fused to a small molecule to create ADCs. Fc-fusion proteins confer the advantages of IgG, including binding to the neonatal Fc receptor (FcRn) to facilitate in vivo stability, and the therapeutic benefit of the specific effector functions45. Today, there are eight approved Fc-fusion proteins. ADCs harness the specificity of mAbs to selectively deliver highly potent cytotoxic drugs to tumour cells that express a particular antigen on their surface, thereby reducing damage to healthy tissues46. As with BsAbs, there have been challenges in realizing the potential of the ADC strategy, with only a few ADCs for blood cancers approved so far, but the field is active, with more than 50 ADCs in clinical trials47.

Clinical successes and approvals

The number of mAb-based therapies approved for rare diseases outside the oncology field is limited at present, but the potential of the platform for highly specific targeting of disease-linked proteins is beginning to be realized. This therapeutic modality has been primarily developed for large indications and then repurposed, initially off-label, for some rare disease indications. We highlight a few illustrative examples here.

Eculizumab, a mAb that targets the terminal complement protein C5, was first approved for paroxysmal nocturnal haemoglobinuria more than a decade ago, and has since been approved for two other rare diseases in which the complement system has an important role: atypical haemolytic uraemic syndrome and myasthenia gravis. Canakinumab, a mAb targeting the pivotal inflammatory cytokine IL-1β that was originally developed for rheumatoid arthritis48, was repurposed and approved for cryopyrin-associated periodic syndromes in 2009. It has since been tested in clinical trials for other diseases, including an ‘umbrella trial’ that provided the basis for its approval for three rare other periodic fever syndromes linked to IL-1β49. IL-1β is also the target of rilonacept, a fusion protein consisting of the ligand-binding domains of the extracellular portions of the human IL-1 receptor component and IL-1 receptor accessory protein linked to the Fc portion of human IgG1, which was approved for cryopyrin-associated periodic syndromes in 2008 (ref.50).

One of the two BsAbs approved so far is for a rare disease: the haemophilia therapy emicizumab acts by binding to factor IX and factor X, bringing these proteins close to each other and initiating a coagulation cascade51. The pioneering nanobody therapeutic caplacizumab, which targets von Willebrand factor, has recently been approved in the European Union and in the United States for acquired thrombotic thrombocytopenic purpura52.

Strengths and limitations as a platform for rare disease therapies

A key strength of mAb-based therapies as a platform in general is their high specificity. This limits the risk of off-target toxicity, which is frequently observed with small molecules. This is particularly relevant in the treatment of rare diseases, which often involves long-term drug administration. Related to this, another advantage of mAbs is that their stability in vivo allows infrequent (for example, once-monthly) dosing regimens in such contexts. For rare diseases caused by ‘gain of function’ of a particular protein that is present in the circulation and/or on the surface of cells, approaches to identify suitable mAb therapies are well established. Importantly, some approaches such as phage display are becoming increasingly accessible not just to major biopharma companies but also to small and medium-sized enterprises and universities53. Furthermore, other functionalities are also possible for mAb-based therapies, demonstrated earlier by the example of the BsAb emicizumab, although such approaches are less straightforward to pursue.

However, the large size of mAbs limits their tissue and cell penetration, preventing the pursuit of some theoretically desirable targets such as intracellular proteins, although this is one area in which novel fragment formats such as nanobodies hold promise. The manufacturing costs for mAbs may also be prohibitive owing to the need for large cultures of mammalian cells followed by extensive purification steps, under good manufacturing practice conditions. In addition, mAbs need to be injected (with the consequent need for very high standards of sterility in the formulation phase), and may initiate injection-site adverse reactions — a feature they share with other large molecules such as those used in protein replacement therapies (see the next section).

Although the mAb platform is currently only marginally deployed in rare conditions, its future will probably look different owing to two major developments. First, the capability to identify and manufacture mAbs efficiently and safely is ‘democratizing’. That, together with the much higher mAb titres that can be achieved today in batch, fed-batch or continuous perfusion cell culture, is greatly reducing the cost of goods and the flexibility of use of moderately sized good manufacturing practice upstream and downstream manufacturing suites54.

Second, the entry into the market of cheaper biosimilar versions of pioneer mAbs may facilitate repurposing efforts (see later). For example, the use of artificial intelligence to match the mechanisms of action of well-characterized mAbs with pathway information derived from large sequencing efforts (such as Genomics England) implicated in rare diseases might benefit patients with rare diseases that currently lack therapeutic options.

Protein replacement therapies

While the mAb platform discussed in the previous section is well suited to the development of therapies for rare diseases linked to gain of function of a particular protein, another biologic platform — protein replacement therapies — has long been a cornerstone in the treatment of rare diseases linked to the loss of function of a particular protein. One prominent example is the administration of factor VIII or factor IX to treat patients with haemophilia A or haemophilia B, respectively. This area has seen substantial innovation in the past few decades, progressing from plasma-derived products to recombinant proteins, to recombinant engineered proteins that have superior therapeutic characteristics, including modifications such as pegylation, to the latest advances such as emicizumab. These developments have been comprehensively reviewed recently55, so we focus here on a broad strategy — ERT — to illustrate the platform.

Diseases caused by missing or defective enzymes can be treated by replacement with exogenously supplied enzymes, either purified from human or animal tissue or produced by recombinant techniques56. The concept of systemic delivery of a deficient enzyme to rescue cellular function in patients with LSDs goes back to the 1960s29,57,58, but the first ERT to be developed successfully was human α1-antitrypsin (A1AT) to treat emphysema associated with severe A1AT deficiency59, which was approved by the FDA in 1987 (ref.60).

The focus of most ERT development so far though has been various LSDs, which are genetic diseases caused by missing, insufficient or malfunctioning enzymes in the lysosomes, leading to a pathological build-up of their substrates29,58,61. LSDs are progressive, and often ultimately fatal, although characterized by a spectrum of clinical manifestations, with variable disease progression rates, and beginning in fetal life. In the 1980s, Brady and colleagues at the US National Institutes of Health provided the proof of principle for ERT to treat LSDs by showing that glucocerebrosidase purified from placentae could be used to treat Gaucher disease62. Purified human placental glucocerebrosidase was further developed by Genzyme and first approved as a commercial ERT by the FDA in 1991. For safety and supply reasons, Genzyme developed a recombinant form of glucocerebrosidase, which was first approved by the FDA in 1994.

Technology summary

Enzymes used for ERT are either natural forms or recombinant proteins showing a high degree of homology with the human enzymes. The emergence of HIV/AIDS as well as potential supply limits made the use of natural enzymes less desirable. Therefore, most enzymes used in ERT are recombinant, which also allows modifications to provide a longer half-life, more potent activity, resistance to degradation or targeting to a specific organ, tissue or cell type57.

ERTs are typically produced using mammalian cell lines, most commonly Chinese hamster ovary (CHO) cells, although modified human cells are also used. Prokaryotic systems are not useful for the expression of lysosomal enzymes because they cannot perform the post-translational modifications (such as N-linked glycosylation and mannose phosphorylation) needed for lysosomal enzyme stability, synthesis and/or activity61,63. An exception to the main use of CHO cells is the production of taliglucerase alfa in plant (carrot) cells in suspension, which does not require additional processing for glycosidic modifications64. As with all recombinant protein therapeutics, purification of the manufactured enzymes from the bioreactor broth is complex and needs to be highly controlled to preserve the biological activity of the final product and to ensure sufficient yield. Also, changes in manufacturing parameters such as the scale of the bioreactor can cause differences in the characteristics of the final product that may be considered clinically meaningful by the regulators, as exemplified by alglucosidase alfa, an ERT for Pompe disease. The product derived from two sizes of bioreactor has been approved by the FDA under two different trade names, whereas products from both sizes of bioreactor were considered sufficiently identical from a clinical perspective by the European Medicines Agency (EMA) to be approved under the same name.

Clinical successes and approvals

The emergence of ERTs for some LSDs has made it possible to treat patients and save their lives58,61. Recombinant ERTs have been developed and approved to date for 11 different LSDs worldwide (10 approved by the FDA, 9 approved by the EMA), including Gaucher disease, Fabry disease, Hurler–Scheie disease (also known as mucopolysaccharidosis type I (MPS I)), Hunter disease (MPS II), Pompe disease, Maroteaux–Lamy disease (MPS VI), lysosomal acid lipase deficiency (Wolman disease), Batten disease (neural ceroid lipofuscinosis type 2), Morquio A syndrome (MPS IVA) and recently Sly disease (MPS VII) and α-mannosidosis. For some LSDs, more than one commercial ERT is available. Several ERTs are in development for additional LSDs, including Sanfilippo A syndrome (MPS IIIA) and Sanfilippo B syndrome (MPS IIIB)56,65,66. Outside the field of LSDs, a few ERTs have been approved for A1AT augmentation therapy67 and for adenosine deaminase (ADA) deficiency-associated severe combined immunodeficiency disease (SCID)68, using natural (human and animal) enzymes, and recombinant ERTs were approved for hypophosphatasia (in the United States and the European Union), and phenylketonuria (in the United States)69.

Strengths and limitations as a platform for rare disease therapies

On the basis in part of 20 years of experience using ERT to treat more than 5,500 patients with type 1 Gaucher disease, the following general points can be made about ERT as a platform61.

First, ERT can be very effective if the replacement enzyme can be delivered at the right dose into the right tissue and cells early enough in the course of the disease (that is, before major irreversible organ damage has occurred)56,58,61. Enzyme delivery is receptor mediated and dose dependent, and in Gaucher disease, mannose molecules on the enzyme surface help the enzyme enter the relevant cell type, macrophages58,61. However, for other LSDs, such as mucopolysaccharide disorders, Fabry disease and Pompe disease, ERT proved more difficult to develop because pathological substrate build-up occurs in other cell types that lack or express low levels of mannose receptors58,64. In addition, when the enzyme needs to be delivered into organs or tissues less served by the vascular system, much higher amounts may be needed. For example, in Pompe disease, skeletal muscle cells have low levels of mannose receptors, so very high amounts of enzyme (20–40 mg kg−1) are necessary to achieve the right therapeutic effect63,70,71. In addition, intravenous ERT is not effective for neurological manifestations of the neuropathic subtypes57,58,61, as enzymes are too large to cross the blood–brain barrier. ERT with intrathecal injections into the CNS is therefore being tested in some LSDs57,72.

Second, the safety record of ERT is excellent. Very few patients experience significant infusion-related reactions. Hypersensitivity can be a difficult problem however, not just causing allergic reactions but potentially also limiting the efficacy of therapy owing to the formation of antibodies to the recombinant enzyme, and in severely affected patients with irreversible organ damage, ERT may not have any therapeutic effect57,58. Overall, the relevance of antidrug antibodies specific to ERTs for LSDs remains a mixed picture that will require time and continued clinical follow-up to resolve for each specific condition and treatment57,73.

Third, technologies for ERT are well developed, but will continue to have limitations, including the cost of manufacturing and of purification of recombinant enzymes and the time to build manufacturing capabilities for new products. ERT dosing (~1 mg per kilogram body weight for Fabry disease, MPS and Gaucher disease, versus 20–40 mg kg−1 in Pompe disease therapy) will remain an important factor in determining the size of the manufacturing facility required.

Looking to the future for ERT, the establishment of relevant study end points in clinical trials for ERT is of growing importance, together with the understanding of what comprises a minimal clinically important difference in these end points for the patients. It may be insufficient to use subclinical parameters rather than clinical outcomes or to evaluate end points for which relevance to patients’ outcomes remains unclear58,61,72. LSDs are likely to remain a strong focus in the near future, as of the 70 or more of these rare monogenic diseases (which collectively affect 1 in 5,000 live births)29, ‘only’ 11 of them have an approved ERT. Nevertheless, the monogenic nature of LSDs and the detailed knowledge of the function of many of the proteins defective in these disorders provide multiple therapeutic intervention points29,72 and so several alternatives to ERT are being developed or investigated. These include small-molecule strategies mentioned earlier, stem cell transplants and gene therapy mentioned later, which would potentially allow the 70% of LSDs with neurological involvement to be addressed29,57,58,61,66. Combination therapies are being tested as well58. Therapies that target converging elements of the pathogenic cascade and thus may be applicable to more than one LSD may also be considered but may be less effective29,72. The challenges and successes of therapy development for LSDs may inform the treatment for other rare diseases29.

Oligonucleotide therapies

Another broad strategy to specifically target disease-associated genes is to intervene at the level of RNA. Several approaches to targeting RNA have been developed, with the most extensively investigated of these being ASOs and siRNAs, which can both reduce the production of a specific disease-associated protein by promoting degradation of its mRNA. Like antibodies, ASOs and siRNAs can be highly specific interventions for rare diseases with a well-defined molecular cause, with the additional advantage that in principle any gene product can be targeted, rather than just cell-surface or circulating proteins. The development of ASOs and siRNAs has been a long and challenging process, particularly with regard to delivery, but recent approvals and an extensive clinical pipeline indicate that these platforms are now poised to fulfil their potential.

Technology summary

Oligonucleotide therapies are synthetic nucleic acid sequences that bind to RNA targets through sequence-specific base pairing and thereby affect gene expression in various ways. The first oligonucleotide therapies to be investigated were ASOs, for which research began in the late 1970s. ASOs are single-stranded molecules that bind to complementary mRNA by Watson–Crick base pairing, and initiate its selective degradation by ribonuclease H, leading to knockdown of the expression of the corresponding protein. The identification of various chemical modifications, such as phosphorothioate backbones to increase the resistance of ASOs to degradation by nucleases in vivo, has also been crucial in developing ASOs as a robust platform for gene knockdown74.

The second class of oligonucleotide therapies that degrade target mRNAs are synthetic siRNAs, which are based on the discovery of RNA interference as an endogenous mechanism for gene regulation in 1998 (ref.75). While these are double-stranded rather than single-stranded like ASOs, they also incorporate modified chemical backbones to enhance their pharmaceutical properties. Delivery has been a greater challenge for siRNAs than ASOs, and to address this, they are also typically conjugated to carriers such as lipid nanoparticles or N-acetylgalactosamine, with most siRNA drug candidates so far exploiting the ability of such carriers to achieve delivery to the liver76.

A third class of oligonucleotide therapies act in a different way, hybridizing to pre-mRNAs or mRNAs without leading to their degradation77. Depending on the nature of the interaction, these single-stranded RNA-blocking agents (which are also chemically modified as with ASOs and siRNAs) can have various effects that may be useful in the treatment of rare disorders linked to gene dysfunction, such as exon skipping, cryptic splicing restoration or even changing levels of alternate gene splicing78. Importantly, gene function can be restored by such therapies, in contrast to ASOs and siRNAs, which only inhibit gene function.

Clinical successes and approvals

Oligonucleotide therapies have demonstrated clinical efficacy for the treatment of multiple human diseases, with the first FDA approval of an ASO in 1998, fomivirsen for cytomegalovirus retinitis in immunocompromised patients, including those with AIDS, an orphan condition79. Although fomiversen has since been withdrawn, other ASOs have followed, such as the ASO mipomersen, which was approved in 2013 for familial homozygous hypercholesterolaemia; this ASO targets mRNA for apolipoprotein B-100, the principal apolipoprotein of LDL and its metabolic precursor, VLDL80.

However, the application of oligonucleotide therapies is perhaps most promising in rare neurological conditions81, which has led to several pioneering approvals in recent years. Two of the approved products harness different platforms for the treatment of hereditary transthyretin (TTR)-mediated amyloidosis. Patisiran, a lipid-conjugated siRNA, became the first siRNA therapy to be approved by the FDA (in 2018)82, and this was followed shortly after by the FDA approval of the ASO inotersen83. Both agents act by degrading the mRNA encoding TTR, resulting in a reduction in serum TTR and TTR deposits in tissues84 and clinically relevant improvements in the neurological manifestations of hereditary TTR-mediated amyloidosis.

Two further RNA-blocking oligonucleotide therapies have also been approved for rare neurological conditions. Nusinersen was designed to treat SMA caused by mutations in chromosome arm 5q that lead to SMN deficiency. It acts by increasing exon 7 inclusion in SMN2 mRNA transcripts, resulting in the production of full-length SMN85,86 and has been approved in the United States and the European Union. Eteplirsen was designed to hybridize to exon 51 of dystrophin pre-mRNA, leading it to being skipped during splicing, and thereby correcting the translational reading frame and resulting in the production of shortened, but functional, dystrophin proteins in patients with DMD76,77. However, there has been controversy over the extent to which dystrophin function is restored by treatment with eteplirsen in trials conducted so far, and while the FDA granted approval for eteplirsen in 2016, a marketing authorization application to the EMA received a negative opinion in 2018.

Strengths and limitations as a platform for rare disease therapies

The mechanistic characteristics of oligonucleotide therapies result in high specificity, ability to address targets that are otherwise inaccessible with traditional therapies and reduced toxicity owing to limited systemic exposure81. This greatly expands the numbers and types of selectable targets81. With the majority of the known rare diseases being of genetic origin, RNA targeting by oligonucleotide therapies provides a key opportunity to reduce the vast morbidity and mortality associated with rare conditions87. However, the fact that oligonucleotides do not readily cross the blood–brain barrier, and therefore require invasive delivery methods such as intrathecal or intraventricular routes, remains one of the most substantial obstacles for their clinical applications in CNS disorders. Despite this, the number of recent successes that resulted in regulatory approval are likely to result in greater research and development for other rare conditions. For example, an ASO that targets the mRNA for huntingtin (HTT), known as RG6042, has recently entered phase III trials for Huntington disease in the hope that this may represent the first disease-modifying therapy for this neurodegenerative disorder88.

Gene and cell therapy

Gene therapy harnessing viral vectors can be used in two general contexts for rare diseases. For diseases in which the therapeutic goal is to compensate for a loss of function of a particular protein, such as in SMA, the vector is used to express a transgene (with the endogenous sequence or codon optimized) that encodes the desired protein, under the control of an appropriate promoter. Conversely, for diseases such as Huntington disease, where the aim is to suppress the impact of a pathogenic gene, a transgene that encodes an RNA (such as a short hairpin RNA) that can harness RNA interference mechanisms to inhibit gene expression can be introduced.

There are also two broad approaches for delivery of gene therapy, depending in part on the cells in which the gene needs to be expressed to treat disease. In some cases, viral vectors containing the therapeutic gene can reach the desired cells following injection of the vector, often directly into the tissue or organ, such as the eye, which can promote uptake and minimize off-target effects. In other cases, cells are genetically modified outside the body to produce therapeutic factors and subsequently transplanted back into patients. This ex vivo gene therapy approach, which can also be considered as a type of cell therapy, is particularly useful for rare inherited blood disorders, for which haematopoietic stem cells (HSCs) can be collected from patients, genetically modified and then transplanted back into patients.

Other types of cell therapy are also being developed for rare diseases, including transplants of cells derived from iPS cells, such as retinal cells for eye disorders, and chimeric antigen receptor (CAR) T cells that target specific tumour antigens for rare cancers. Cells can be injected or incorporated onto scaffolds for placement in the appropriate tissue, such as the eye.

Technology summary

Two gene therapy platforms based on viral vectors have emerged as the most useful for clinical studies in rare diseases: adeno-associated virus (AAV) vectors and retroviral/lentiviral vectors89.

With recombinant AAV vectors, a therapeutic transgene, including the promoter and other regulatory elements, of up to five kilobases in size can be inserted into the AAV for gene therapy applications. Thirteen different AAV serotypes have been identified, reflecting different amino acid sequences of the capsid proteins. These differences result in differing tropism for different organs, tissues and cell types90. On the basis of clinical studies, certain AAV serotypes are emerging as tissue-specific platforms. For example, AAV-8 has been used in three clinical trials for gene delivery to the liver, while AAV-9 has been used in four trials in neurological diseases. On the basis of available crystal structures of capsid proteins, it is now possible to rationally engineer novel capsids in an effort to develop vectors to target specific cells and tissues91,92. AAVs can infect both dividing and non-dividing cells. Although wild-type AAV can integrate into the human genome, sequences encoding the viral proteins necessary for integration are deleted in AAV vectors used for gene therapy. Therefore, recombinant AAV vectors are generally considered to be non-integrating — a very important feature with regard to potential safety issues from a regulatory perspective. However, the lack of integration means that AAV vectors will be lost from infected cells as they replicate. For this reason, AAVs are primarily used for gene therapy in non-dividing (or very slowly dividing) cell types.

With regard to safety, it is worth emphasizing that, despite the similarity in name, AAVs are fundamentally different from adenoviruses (the viral vector used in a gene therapy trial in the 1990s that resulted in the death of a patient with a rare disease). Whereas adenoviruses are human pathogens, AAVs are not known to cause any human disease. AAV vectors have an excellent safety record, having been used in more than 200 human clinical trials93 without any deaths or without causing cancers. Some recent studies have linked AAV vectors to an increased risk of liver cancer in mice94, although the relevance of these findings for human cancer is the subject of debate95. The most common serious adverse effect resulting from AAV vectors in humans is a transient elevation of the level of liver transaminase (indicative of liver damage), which is related to an immune response to the AAV capsid proteins. However, this can generally be controlled by a course of steroid treatment96.

Retroviruses contain a single-stranded RNA genome and have the capacity to integrate into the human genome via a mechanism involving reverse transcription. The ability to integrate allows the possibility of permanent modification of the genome, which will persist over time and following cell replication. Lentiviruses are a genus of the retrovirus family. However, in contrast to other types of retroviruses, the entry of lentiviruses into the cell nucleus does not depend on mitosis. As a result, lentiviruses can be used to deliver genes into both dividing and non-dividing cells.

Initial investigations of retroviruses for gene therapy focused on disorders of blood cells, using an ex vivo approach. Retrovirus vectors based on murine leukaemia virus were used in some early trials, but these were plagued by poor efficacy. Subsequent work using other gammaretroviruses demonstrated substantial clinical efficacy in ADA deficiency-associated SCID, such that the patients were able to stop ERT. However, patients administered gammaretroviral vectors in X-linked SCID and Wiscott–Aldrich syndrome trials and in an X-linked chronic granulomatous disease trial developed leukaemias due to integration of viral vectors adjacent to oncogenes, resulting in transcriptional activation by powerful enhancer elements present in the long terminal repeats of the viral genome. To avoid these problems, the field turned to lentiviral vectors due to their greater efficiency for infecting human HSCs97. Specifically, self-inactivating lentiviral vectors, in which critical transcriptional enhancer sequences in the long terminal repeats are deleted in the course of vector production98, have emerged as a platform for ex vivo gene therapy using HSCs97,99.

Depending on the initial cell source, cell therapies are categorized as patient specific (most often autologous but also allogeneic) or off the shelf (allogeneic). ‘Active ingredients’ differ widely, including T cells, dendritic cells, HSCs, mesenchymal stromal cells, CD34-selected cells, islet cells, fibroblasts, natural killer cells, neural stem cells, embryonic stem cells and iPS cells. Source cells are modified through processes that include some combination of target cell isolation (selection, sorting), culture (expansion and activation), washing, volume reduction and formulation. Cryopreservation may or may not be used to extend the shelf life of incoming cells, intermediate products or finished product. iPS cells have generated a lot of interest due to their ability to differentiate into many different cell types that can target many disease indications100. These cells can be reprogrammed from an autologous sample (for example, dermal tissue) before being differentiated into the target cell type, such as retinal cells for eye disorders101.

For genetically modified cells, ex vivo modification is typically achieved through the use of viral vectors, as discussed above. Diseases for which ex vivo modification of target cells is feasible are also at the forefront of approaches to the clinical translation of gene editing technologies such as zinc-finger nucleases and CRISPR–Cas9-based approaches102. This is in part due to the substantially lower risks of deleterious off-target editing in this context compared with genome editing in vivo. The approaches being taken are exemplified by the development of potentially curative treatments for sickle cell disease and β-thalassaemia, which are caused by mutations in the β-globin gene that compromise production of normal adult haemoglobin. Pioneering trials are investigating ex vivo gene editing of HSCs before reinfusion103. One such approach involves CRISPR-induced disruption of BCL11A, a repressor of the γ-globin gene, which allows expression of compensatory fetal haemoglobin. A trial in patients with β-thalassemia began in 2018, and a trial in patients with sickle cell disease began in 2019.

Clinical successes and approvals

AAV-based therapies have demonstrated clinical efficacy for the treatment of multiple human diseases, including SMA104, haemophilia A and haemophilia B105, aromatic l-amino acid decarboxylase deficiency and retinal pigment epithelium-specific 65-kDa protein (RPE65)-mediated retinal degeneration. Three AAV-based gene therapies have been approved for the treatment of rare diseases so far, all due to loss of gene function. Alipogene tiparvovec is an AAV-1 vector that expresses the gene for lipoprotein lipase that is administered by intramuscular injection. It became the first gene therapy to be introduced in a major market, with its approval by the EMA in 2013 for the treatment of lipoprotein lipase deficiency106, but was withdrawn in 2017 owing to commercial issues. More recently, voretigene neparvovec, an AAV-2 vector that expresses the RPE65 gene, received FDA approval for the treatment of RPE65 mutation-associated inherited retinal dystrophy107 in 2017 — the first gene therapy to be approved in the United States — and shortly after also received approval in the European Union108. In 2019, it was joined by onasemnogene abeparvovec, an AAV-9 vector that expresses the gene encoding SMN (SMN1), which has received approval for the treatment of SMA in the United States and is under regulatory review in the European Union.

Clear evidence of clinical efficacy without malignancy has been observed in studies using a gammaretroviral vector for ADA deficiency-associated SCID, and with self-inactivating lentiviral vectors for other haematological disorders, including X-linked SCID109, Wiscott–Aldrich syndrome110 and β-thalassaemia111. Strimvelis, a retrovirus that expresses ADA, became the first ex vivo gene therapy to be approved for a rare disease when the EMA granted its approval for the treatment of ADA deficiency-associated SCID in 2016 (ref.112). A lentiviral platform has shown clinical success in treating three neurological diseases: X-linked adrenoleukodystrophy113, metachromatic adrenoleukodystrophy114 and cerebral adrenoleukodystrophy115.

In 2017, two CAR T cell therapies were approved in the United States for rare cancers: tisagenlecleucel116 for acute lymphoblastic leukaemia and axicabtagene ciloleucel for large B cell lymphoma117. Clinical data for these approaches have demonstrated transformative efficacy: patients receiving axicabtagene ciloleucel in the phase II ZUMA-1 pivotal trial achieved an overall response rate of 72%, while patients receiving tisagenlecleucel in the phase II ELIANA pivotal trial achieved an overall response rate of 83% — responses previously unheard of in haematological cancers. While the rapidly growing pipeline of CAR T cell therapies118 are not being developed only for specific rare cancers (indeed, the hope is that they will be much more broadly applicable), their development has helped establish the processes and regulatory requirements for cell therapies more broadly.

Finally, in June 2019, a product for the treatment of β-thalassaemia based on autologous CD34+ cells encoding the βA-T87Q-globin gene was conditionally approved by EMA.

Strengths and limitations as a platform for rare disease therapies

On the basis of the clinical experience to date, AAV vectors appear to be an excellent platform for treating rare monogenic disorders119. AAV vectors have shown clear evidence of clinical efficacy in multiple diseases of the nervous system, the retina and the liver. These results, as well as studies in animals, indicate that AAV vectors can support transgene expression that persists for years in non-dividing cells. A key limitation is the complexity and cost of manufacturing and production, which are vastly greater than for small molecules. Other limitations of AAVs include the potential loss of AAV-transduced cells due to immune responses, lack of effective vector serotypes for other relevant tissues and cell types and the limited capacity of the genome.

AAVs can also be used to deliver genome editing enzymes such as Cas9 or zinc-finger nucleases to treat rare diseases120. Indeed, AAV vectors were used to deliver zinc-finger nucleases in the first clinical trial of genome editing in a rare genetic disease121. However, while gene therapy requires long-term expression of a therapeutic gene, which is supported by AAV vectors, long-term expression of genome editors after genome editing has been completed may have negative consequences. Therefore, non-viral delivery vehicles such as lipid nanoparticles are of increasing interest for delivering genome editors122.

Retroviral vectors have been shown to be effective clinically for ex vivo gene therapy for haematological diseases123. A major limitation to the use of retroviruses has been carcinogenesis resulting from integration of the vector into the genome. However, no malignancies have been observed in clinical studies using self-inactivating lentiviral vectors to date, suggesting that this problem has been addressed, although careful observation of treated patients for signs of clonal expansion will be required. Another clinical consideration is the requirement for myeloablative conditioning before infusion of the gene-modified HSCs, which is associated with significant toxic effects.

A key limitation for the use of cells as therapies is the current incomplete ability to characterize such products to ensure consistency, and the precise mechanism of action for these products may also not be clear. This limitation places extreme pressure on making improvements to the chemistry, manufacturing and controls (CMC) for cell therapy candidates, which, due to the early stage of development of the industry, often includes reliance on open and manual technologies. The pressure to maintain quality, as is necessary to achieve patient safety, comes at the expense of scalability and sustainability. These factors increase the cost of goods for these therapies, especially for patient-specific cell therapies, to a level that is unsustainable in the long term124. There is therefore a need for biologists and engineers to collaborate on further developments in both clinical and CMC aspects to solve these challenges, as has been achieved with other biologic platforms discussed above.

Overall, gene and cell therapies as a platform are at an early stage of development compared with small molecules, antibodies and protein replacement therapies. In addition, the complexity and cost of manufacturing viral vectors and cell therapies are much higher than for small molecules. Nevertheless, the possibility that such therapies could be a one-time treatment or even a cure for a disease has profound implications for the development of rare disease therapeutics.

Drug and target repurposing

Drug repurposing (also called drug repositioning, drug rescue, reprofiling, retasking or therapeutic switching) involves the evaluation of approved or investigational drugs to treat a condition different from that for which the product was previously approved or clinically investigated125. Most repurposed compounds have already demonstrated safety in humans, and some have progressed into phase II or phase III trials126. So, in theory, such molecules could be clinically tested in alternative indications, providing a path to an approved drug that is quicker, less risky and less costly than for completely new drugs.

Technology summary

Historically, drug repurposing opportunities have often been identified through astute serendipitous clinical observations, compassionate-use programmes and off-label prescriptions. More than a quarter of all annotated drugs and therapeutic uses are annotated with off-label prescriptions (27% (641 of 2,371) of the active pharmaceutical ingredients as well as 27% (817 of 2,984) of the total therapeutic uses)127. The successes have fuelled interest in more systematic strategies to identify repurposing opportunities. These can be broadly categorized into experimental approaches and computational approaches128. Experimental approaches include molecular profiling to identify additional rare-disease-relevant targets for approved drugs and for clinical trial candidates, as well as phenotypic screening of libraries of such compounds. The aim is to accelerate the translation of hits into clinical trials for rare disease indications. Computational approaches include systematic retrospective analysis of clinical trial data, electronic medical records and/or postmarketing surveillance data aiming at identifying unexpected signals that might be relevant in the context of other diseases, in addition to virtual screening and similarity-based methods. For example, translational bioinformatics129,130 can deploy networks and systems biology methods131 combined with machine learning to infer novel relationships between biomolecules and clinical observations to postulate new functions and roles in disease for proteins. Emerging online platforms are likely to increase the impact of translational bioinformatics in the discovery of novel therapeutic targets and pathways for rare diseases (Box 2).

Clinical successes and approvals

Repurposing and extension of existing indications has often been successful. Two examples where drugs originating from different platforms discussed earlier have gained additional approvals for rare disease indications following initial approval for a common condition are sildenafil and adalimumab. Sildenafil is a small-molecule phosphodiesterase 5 inhibitor that was initially approved for erectile dysfunction in 1998 as a result of repurposing during clinical development from its original indication, angina132. On the basis of its effects on vascular biology, it was subsequently also repurposed for a rare disease, pulmonary arterial hypertension133, leading to its approval for this indication in 2005. Adalimumab is a mAb that targets the pivotal inflammatory cytokine tumour necrosis factor (TNF), and was first approved in 2002 for rheumatoid arthritis. It has since gained further approvals for several other inflammatory diseases, some of which are rare, including polyarticular juvenile idiopathic arthritis in 2008 and non-infectious intermediate, posterior uveitis and panuveitis in 2014.

Other repurposing candidates have entered clinical trials, including some from programmes that have been established to support repurposing. Initiatives focused on rare diseases include the International Rare Diseases Research Consortium (IRDiRC) and E-Rare in the European Union (see Related links). In 2016, a European Research Area Networks call for proposals emphasized the repurposing needs. IRDiRC has developed a preliminary report to identify opportunities for repurposing of existing compounds in rare diseases, and repurposing is a key mechanism to reach its 2027 goal to develop 1,000 new therapeutic uses for rare diseases.

Programmes that support drug repurposing in general include the New Therapeutic Uses (NTU) programme134 and the Bridging Interventional Development Gaps (BrIDGs) programme at the US National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (see Related links), and a partnership between the UK Medical Research Council and AstraZeneca, both of which involve collections of clinical-stage compounds that have been discontinued by pharma companies for their original indication. While most of the compounds that have progressed to clinical trials in these programmes so far are for common diseases, there is also substantial potential for repurposing for rare diseases. For example, through the Medical Research Council–AstraZeneca programme, the 11β-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 is being evaluated in a phase II trial for idiopathic intracranial hypertension135. Finally, the European Commission Expert Group on Safe and Timely Access to Medicine for Patients (STAMP) has recently published a draft proposal for a framework to support not-for-profit organizations in drug repurposing.

Strengths and limitations as a platform for rare disease therapies

Drug and target repurposing creates the potential for academic institutions and patient advocacy organizations to get involved in translational research on compounds that have established clinical profiles for other diseases already. Public and private sector initiatives have been started to allow screening of approved and investigational products to optimize product selection for investigation in rare diseases. In addition to those mentioned already, the NCATS Division of Preclinical Innovation has developed the NCATS Pharmaceutical Collection, which includes ~2,500 compounds approved for use by the FDA and 1,000 compounds approved for human clinical research investigations136. Another compound collection is the Broad Institute’s Repurposing Hub Screening Library, which contains comprehensive annotations for ~6,000 compounds, including ~2,300 approved drugs, and ~1,600 drugs that reached clinical development. This library is available for collaborative screening activities137 (see Related links).

However, not all potential challenges in drug development are removed with repurposing126,137. First, although repurposed drug candidates may have a greater chance of success and lower development costs owing to the availability of safety data and better understanding of their clinical effects than typical investigational drugs, clinical trials to demonstrate efficacy in the new indication are still needed, and these may require substantial further investment. Second, although safety data on a candidate for drug repurposing may be available for the original indication, the safety profile of a drug might dramatically change in the presence of a different set of conditions characterizing the new indication (for example, comorbidities) or treatment regimen (for example, long term versus short term). The clinical safety of the repurposed drug/target in the new indication should therefore be carefully evaluated. Third, ownership of intellectual property rights or lack thereof may delay access to compounds for clinical evaluation and reduce incentives for companies to invest in drug repurposing efforts.

To address these barriers, the rare diseases community — including academic institutions, industry, patient advocacy groups, foundations, payers and government regulatory and research organizations — must be engaged as a partnership in discussions about issues such as access to data from electronic medical records and development of patient-reported clinical outcomes. Developing a repurposing platform for rare disease therapies requires a change in traditional approaches of investigating one product for one disease at a time.

Closing perspectives

Having presented the main platforms that can already be applied to the development of new drugs for rare diseases, we will conclude by briefly highlighting some of the key issues that affect the environment in which such drugs are developed. Some of these issues have been discussed extensively elsewhere, and we refer readers to such articles for further details138,139.

Regulatory pathways for orphan product development

Various regulatory pathways and economic incentives to facilitate the development of products to treat or diagnose rare diseases are now established in the United States, Europe, Japan and elsewhere139 (Box 1). There are many similarities between such regulations and collaboration between regulatory agencies in terms of how orphan drugs may be developed and rare diseases may be supported, but there are important differences and also continuing misconceptions about the underlying regulations2.

Several regulatory initiatives have been introduced to increase the speed of development of innovative products that have the potential to address major unmet medical needs. These include the fast track pathway, accelerated approval, priority review, breakthrough therapy designation and regenerative medicine advanced therapy designation in the United States and conditional marketing authorization, approval under exceptional circumstances, accelerated assessment, the Priority Medicines (PRIME) scheme and the advanced therapies regulation in the European Union. These programmes can be used (in some cases, together) for therapies for both rare and more common diseases. However, a review of approvals by the FDA and the EMA shows that these programmes are used more for orphan drugs than for products for non-rare diseases (Table 1).

Table 1 Use of expedited regulatory review pathways for orphan drugs

Patients’ engagement in regulatory decision-making and orphan drug development

Patients’ advocacy groups continue to expand their role as research partners in orphan drug development, bringing expertise in areas such as identification of clinical end points, development of informed consent documents and patient recruitment, and participating in meetings with regulatory agencies to discuss research and development activities, as well as benefit–risk assessments in regulatory reviews of medical products. Data on rare diseases tend to be (very) scarce. The emergence of patients’ organizations in the 1980s and 1990s led in the United States by the National Organization for Rare Disorders (NORD), the AIDS Coalition to Unleash Power (ACT UP) and the Alliance for Genetic Support Groups (later called Genetic Alliance) and in Europe by the Genetic Interest Grouping (GIG, United Kingdom; now called Genetic Alliance UK) and VSOP (Netherlands), with their European organization the European Alliance of Genetic Support Groups (EAGS) (now the European Genetic Alliance Network (EGAN)), and later the European Organisation for Rare Disorders (EURORDIS-Rare Diseases Europe) (see Related links), allowed more data collection and deeper knowledge of rare diseases. The FDA and the EMA now use external resources to educate themselves on specific rare conditions. The addition of patients’ representatives on FDA advisory committee meetings in the 1990s and FDA patients’ hearings today, as well as their inclusion in the Committee for Orphan Medicinal Products of the EMA in 2000 and in all subsequently created committees (for example, the EU Patients’ and Consumers’ Working Party140 or the Committee for Advanced Therapies of the EMA) allows patients to be heard in matters of benefit–risk balance and innovation in the regulatory agencies, and now also in health technology assessment bodies and payor settings.

While assessing benefits and risks is crucial at the time of an approval decision, patients’ perspectives can also be invaluable earlier in drug development; for example, in the setting up of patient registries and biobanks and in the selection of clinical trial end points141,142, which are often not well established in rare diseases. Key questions when selecting end points for clinical trials include identifying the right concept to measure, the opportunities that are available to do this in patients’ daily lives and the level of change in the measure that is considered clinically meaningful143. Despite efforts to select and develop fit-for-purpose end points, the heterogeneity in many rare diseases reduces their sensitivity, which when combined with small numbers of patients, can lead to concerns of false negatives. Novel methods have been used that bulwark against such false negatives by capturing patients’ and their caregivers’ perceptions of change using semistructured video interviews that can be implemented before, during and after a clinical trial144. For investigators embarking on orphan drug development, it is important to establish a relationship with patient organizations for the disease that they are working on, which should start as early as possible145.

Promoting effective research and development for rare disease therapies

The numbers of rare diseases and those affected by them indicate that this heterogeneous group of disorders deserves to be a higher public health priority, not by individual disease or disease group, but altogether. While various initiatives have already been set up at the country and international levels (see Related links), all stakeholders in the rare diseases community need to collaborate to bridge the large gap between basic research and therapy development in the field of rare diseases. Today, a large fraction of high-quality research in rare diseases ends without reaching the clinic, and even ends before the preclinical phase. Although the number of orphan drug designations is steadily growing both in the United States and in the European Union (Fig. 1), approved orphan drugs address a small proportion of rare diseases, with only ~5% of them having an approved therapy, meaning that 95% do not have an approved therapy today1. There is also a huge bias towards some disease areas, with more than a third of the total number of orphan drug approvals being for oncology indications (Fig. 3).

Fig. 3: Key figures for rare diseases and orphan drugs.

a | Prevalence (per 10,000 patients) of the diseases for orphan medicinal products authorized by the European Medicines Agency (EMA). b | EMA orphan medicinal product approvals by therapeutic area. c | Frequency distribution of orphan drug approvals from the FDA by the size of the patient population. d | FDA orphan drug approvals by therapeutic area. The approval numbers for the FDA and the EMA are up to the end of 2018. For comparability with the FDA data, the total number of drugs approved as orphan drugs from 2000 to the end of 2018 are used for the EMA data, meaning that the number 187 includes products which have been withdrawn by the sponsor or for which the market exclusivity expired, and also extensions of indications (n = 23). At the end of 2018, there were 112 active market authorizations for orphan medicinal products in the European Union, not including 15 active extensions of the indication.

For rare diseases outside oncology, our assessment is that a major gap exists in the translation of already available science into therapies. Seeking and using standard technology platforms, as well as evaluation mechanisms for the readiness of research programmes as the basis for product development, could potentially empower patient organizations as well as allow progress in therapy development146. Translation of basic research on rare diseases into therapies has to become a much higher priority in public and philanthropic funding. Funding translational stages together with providing advice and support to patients’ groups for the conversion of their research project results into therapy development using the appropriate standards will contribute to the de-risking of early research results, potentially increasingly the likelihood of greater industry engagement in bringing new therapies to market.

The commercial aspects of orphan drug development are crucial for efforts to substantially increase the number of such therapies that reach the market. However, the focus of this article is not the economic drivers or costs of orphan drug development, although they may have a large impact on the price of, affordability/reimbursability of and patients’ access to some orphan drugs, particularly gene and cell therapies. The authors are sensitive to these issues, but they are outside the scope of this article, and are too important and complex to address briefly, so we refer readers to other articles139,147.

A shift in priorities that could be valuable is to move from focusing on what is different about particular rare diseases or their allelic variants to what is common among them — even across disorders with very different phenotypic presentation. This would potentially allow more sustainable and more rapid progress in the translation process to therapies, ideally with multiple disorders treated with the same or a very similar drug. Several work streams are already occurring in this context: designing treatment development programmes directed to molecular and pathophysiologic mechanisms shared by multiple rare diseases72,148 rather than focusing on a single disease. Related to this, the increase in the repurposing of existing compounds is having an impact, as discussed above. Rare monogenic disorders represent a unique opportunity for the application of molecularly targeted differential phenotypic drug discovery in academic settings149,150 as well as of chemical genomics. There may also be promising opportunities for rare disease drug discovery in the understudied regions of the ‘druggable genome’ (Box 2).

Furthermore, sharing diagnostic data in global collaborations while preserving patient privacy will facilitate easier and more rapid diagnosis of rare diseases151, and the creation of common registry and natural history platforms (Box 3) such as the Rare Diseases Registry (RaDaR) programme using common data elements will facilitate cross-disease analyses (see Related links). Data harmonization will result in reduced duplication efforts and costs, and increased efficiency and domain expertise. The increasing availability of sensor technologies, as part of a smartphone or through dedicated wearable devices (Box 4), will constitute a tremendous opportunity to augment data from natural history studies, which will provide value in the identification of drug response patterns potentially shared across very different disorders with similar symptoms. Patients’ groups should be consulted when registries and clinical and natural history studies are being set up to ensure patients’ perspectives are taken into account.

In conclusion, by providing an overview of technology platforms used in drug research and development with a specific focus on rare diseases, we hope that this article will be a valuable resource for anyone interested in the translation of basic science into therapy development for such diseases. We also hope that it will trigger interest in funding and nurturing a culture for translational science to alleviate the suffering of the very large number of patients affected by rare diseases globally.

Change history

  • 08 January 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.


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The authors acknowledge M. Lanthier and K. Miller, who helped formulate FDA data, and M. Gomar Mengod, who helped formulate EMA data for the figures presented. The authors acknowledge work done by the combined teams of C. J. Mungall (Lawrence Berkeley National Laboratory), M. A. Haendel (Oregon Health Sciences University and Oregon State University), P. J. Robinson (Jackson Laboratories) and D.-T. Nguyen (US National Institutes of Health National Center for Advancing Translational Sciences) for Fig. 1 and J. Holmes and S. L. Mathias (University of New Mexico) for the figure related to the rare disease proteome in Box 2. The authors also sincerely acknowledge the help of F. Sasinowsky for the sections on ASOs, natural history and patient engagement, and of E. Powers for the gene and cell therapy section. The authors thank D. Spencer for rereading and commenting on the article. NIH grants U24 CA224370, U24 TR002278, U01 CA239108, UL1 TR001449 and P30 CA118100 provided funding to T.I.O.

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Correspondence to Erik Tambuyzer or Marco Prunotto.

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Related links

Drug repurposing hub:

E-Rare. E-Rare-3 call for proposals 2016:

EURORDIS Rare Diseases Europe:

European Lead Factory:

European Medicines Agency. Committee for Orphan Medicinal Products:

European Medicines Agency. Orphan designation overview:

European Medicines Agency. Rare diseases, orphan medicines. Getting the facts straight:

FDA Rare Diseases Program:

Genetic and Rare Diseases Information Center of the US National Institutes of Health:

IRDiRC. Datamining and repurposing:

Mondo disease ontology:

National Institutes of Health Bridging Interventional Development Gaps Program:

National Institutes of Health Drug Record. Livertox: enzyme replacement therapy:


Orphanet, an online database of rare diseases and orphan drugs:


Rare Diseases Registry (RaDaR) Program:

Supplementary information


Lipinski’s rule of five

These guidelines identify several physicochemical properties to be considered for small molecules that are intended for oral delivery: molecular mass 500 Da or less; five or fewer hydrogen-bond donors; fewer than 10 hydrogen-bond acceptors; and calculated octanol–water partition coefficient (a surrogate for the ability of a molecule to cross biological membranes) of 5 or less.


Gene encoding the cystic fibrosis transmembrane conductance regulator protein, an ion channel in the membrane of cells that produce mucus, sweat, saliva, tears and digestive enzymes. Mutations in CFTR that affect the production, processing or function of the protein underlie cystic fibrosis.

‘Umbrella trial’

A clinical trial design in which a single drug is evaluated in more than one disease simultaneously.


A type of single-domain antibody fragment.

Good manufacturing practice

A system for ensuring that products are consistently produced and controlled according to defined quality standards.


Attaching polyethylene glycol chains to therapeutics, particularly proteins, can improve characteristics such as immunogenicity and pharmacokinetics. For example, pegylation has been used to extend the half-life of factor VIII replacement therapies for haemophilia.

Intrathecal injection

Delivery of a substance directly to the spinal fluid (intrathecal space) through a drug delivery system comprising a pump and a catheter.

Haematopoietic stem cells

(HSCs). Cells that can replenish all blood cell types. HSCs derived from bone marrow have been used for many years to treat cancer; patients receive a myeloablative conditioning regimen to remove diseased cells before transplantation, with the transplanted HSCs then reconstituting the haematopoietic system. A similar strategy can also be used to treat inherited blood disorders.

Adeno-associated virus (AAV) vectors

AAV vectors are based on wild-type AAV, which has a single-stranded circular genome of roughly 4.7 kilobases. The AAV genome contains two open reading frames bounded by inverted terminal repeats into which a transgene of up to approximately five kilobases can be inserted.


A protein shell that originally encloses the viral genome.

Fast track pathway

This can expedite the review of products to treat serious conditions. The process allows sponsors to have more frequent meetings and communications with the FDA to address appropriate data collection and design of clinical trials. It also allows a sponsor to be eligible for priority review and a rolling review of the application.

Accelerated approval

This allows a product for a serious condition to be approved on the basis of a surrogate end point or an intermediate clinical end point. Confirmatory postmarketing trials will be needed to verify this benefit.

Priority review

This is a designation that allows the FDA to act on a marketing authorization application in 6 months (compared with 10 months for standard reviews). To be eligible for priority review, the intended medicine should offer significant advancements in safety and efficacy of treatment, diagnosis or prevention of a serious condition.

Breakthrough therapy deignation

This FDA designation can expedite development of drugs for which preliminary clinical evidence indicates that they may offer substantial advantages over existing treatment options for patients with serious or life-threatening diseases. Designated drugs are eligible for the expedited processing that fast track designation offers, as well as intensive guidance on efficient development from the FDA.

Regenerative medicine advanced therapy designation

This FDA designation is similar to the breakthrough threapy designation and is available for cell therapies, therapeutic tissue engineering products, human cell and tissue products and combination products if the product is intended to treat serious or life-threatening diseases.

Conditional marketing authorization

This European Medicines Agency pathway is similar to the accelerated approval process in the United States. Applicants may be granted a conditional marketing authorization for medicines for which the benefit of immediate availability outweighs the risk of less comprehensive clinical data than normally required.

Approval under exceptional circumstances

In exceptional cases, a reduced data set is acceptable by the European Medicines Agency for candidate drugs for a rare indication with a high medical need if it is difficult to obtain sufficient data to fulfil the requirements of a full dossier for marketing authorization in a reasonable time frame. Annual review of clinical data obtained after such approval is required, with the potential to maintain or withdraw the authorization.

Accelerated assessment

The evaluation of a marketing authorization application under the centralized procedure in the European Union can take up to 210 days. On request, the time frame can be reduced to 150 days if the applicant provides sufficient justification that the medicinal product is expected to be of major public health interest, particularly in cases of therapeutic innovation.

Priority Medicines (PRIME) scheme

A scheme in the European Union that provides early and enhanced scientific and regulatory support for medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options.

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Tambuyzer, E., Vandendriessche, B., Austin, C.P. et al. Therapies for rare diseases: therapeutic modalities, progress and challenges ahead. Nat Rev Drug Discov 19, 93–111 (2020).

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