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Genetic medicines: treatment strategies for hereditary disorders

Key Points

  • Of the approximately 25,000 genes that comprise the human genome, mutations in more than 1,800 have already been identified as causing hereditary disorders.

  • Strategies for genetic medicines — that is, therapies that use the transfer of DNA and/or RNA to modify gene expression to compensate for an abnormal phenotype — include the use of somatic stem cells, gene transfer, RNA modification and, in the future, embryonic stem cells.

  • The main biological barriers to all genetic medicines are delivery and maintenance of the new genetic information. Overcoming these hurdles requires an understanding of: the molecular basis of the disorder, its mode of inheritance, the range of mutations and genotype–phenotype relationships that result in the disease phenotype, how the phenotype is modulated by alternative genes, and how, where and when the disease manifests.

  • Bone marrow stem cell transplantation from individuals that express the normal gene has been used to treat various inherited diseases, including lysosomal storage disorders, immunodeficiencies, haemoglobinopathies and leukodystrophies.

  • Gene transfer of the normal gene to an individual affected by a monogenic disorder is an obvious strategy for genetic medicine. Although many mouse (and larger animal) models of hereditary disorders have been 'cured' with gene transfer, in practice, correcting human hereditary disorders has proved to be difficult.

  • The main thrust in gene-transfer strategies over the next several years will be to develop further: adeno-associated virus vectors for in vivo studies; retrovirus vectors for ex vivo studies that involve autologous haematopoietic stem cells; and probably lentivirus vectors for ex vivo, and possibly in vivo, applications.

  • RNA-modification therapy targets mRNA, either to suppress mRNA levels, or by correcting or adding function to the mRNA using four basic approaches: antisense oligonucleotides, RNAi, trans-splicing and ribozymes.

  • Although mouse hereditary disease models have been corrected by RNAi and trans-splicing strategies combined with gene-transfer delivery, low efficiencies and the requirement to effectively treat most affected cells make the successful application to human hereditary disorders a significant challenge.

  • No genetic medicine has been approved for use in the treatment of any hereditary human disorder, but significant intellectual and economic resources are focused on genetic medicines.

  • The path of development of ground-breaking therapies that we accept as standard today, such as bone marrow transplantation, monoclonal antibodies, in vitro fertilization and organ transplantation were littered by disappointments; similarly, barriers to success in the development of genetic medicines will be overcome, and we predict that, within 10 to 20 years, doctors of genetic medicine will take their place in the front lines of treating human disease.

Abstract

The treatment of the more than 1,800 known monogenic hereditary disorders will depend on the development of 'genetic medicines' — therapies that use the transfer of DNA and/or RNA to modify gene expression to correct or compensate for an abnormal phenotype. Strategies include the use of somatic stem cells, gene transfer, RNA modification and, in the future, embryonic stem cells. Despite the efficacy of these technologies in treating experimental models of hereditary disorders, applying them successfully in the clinic is a great challenge, which will only be overcome by expending considerable intellectual and economic resources, and by solving societal concerns about modifications of the human genetic repertoire.

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Figure 1: Embryonic and somatic stem cells as a source of genetic medicines.
Figure 2: A model for genetic medicine using gene transfer, somatic cell nuclear transfer and stem cell technologies.

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Acknowledgements

We thank R.G. Pergolizzi, J.L. Boyer, N. Hackett and S. Worgall for helpful discussions. We also thank T. Virgin-Bryan and N. Mohamed for help in preparing this manuscript. The studies described in this article that were carried out by the authors were supported, in part, by the US National Institutes of Health; the Will Rogers Memorial Fund, Los Angeles, California; and The Malcolm Hewitt Wiener Foundation, Greenwich, Connecticut.

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Correspondence to Ronald G. Crystal.

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The authors declare no competing financial interests.

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DATABASES

OMIM

adrenoleukodystrophy

Becker muscular dystrophy

Canavan disease

cystic fibrosis

Duchenne muscular dystrophy

Fanconi anaemia

glycogen storage disease type II

haemophilia A

haemophilia B

Huntington disease

metachromatic leukodystrophy

Niemann–Pick A

ornithine transcarbamylase deficiency

sickle cell anaemia

spinal cerebellar ataxia type 1

FURTHER INFORMATION

American Society for Gene Therapy (ASGT) Stakeholder's meeting summary

California Institute for Regenerative Medicine (CIRM)

Clinical Trials in Human Gene Transfer web site

Ensembl

Gene Therapy Advisory Committee (GTAC)

Gene Therapy Clinical Trials Worldwide web site

New Drug Development timeline

Online Mendelian Inheritance in Man (OMIM)

Recombinant DNA Advisory Committee (RAC)

Glossary

Metabolic manipulation

The use of dietary modification or small molecule therapy to compensate for a deranged biological process.

Protein augmentation

A therapy in which a missing protein is replaced by the administration of a protein that has been purified from mammalian cells/tissues or synthesized as recombinant protein.

Phenylketonuria

An autosomal recessive error of metabolism that is caused by lack of the enzyme that converts phenylalanine to tyrosine. It causes abnormally high phenylalanine levels and severe, progressive mental retardation if untreated, but can be prevented by neonatal screening and a low phenylalanine diet from an early age.

'Impeded' androgen therapy

A means to overcome a deficiency in the C1-inhibitor (C1-INH) — a protease inhibitor that is involved in the plasma proteolytic system. The administration of attenuated androgens increases C1-INH expression levels.

Chemical libraries

Collections of tens or hundreds of thousands of organic chemicals, which are commonly referred to as small molecules, that can be characterized for potential utility in specific conditions using high-throughput screening.

Non-autologous

Refers to transplant material that is derived from a genetically independent source. An example is bone marrow transplantation in which the donor and recipient are distinct individuals.

Neuronal ceroid lipofuscinosis

A group of hereditary, fatal neurodegenerative disorders in which the phenotype is limited to the destruction of the retinal epithelium and the CNS.

NOD/SCID

A mouse strain that is derived from the transfer of a severe combined immunodeficiency (SCID) mutation onto a non-obese diabetic (NOD) strain background. This strain is an excellent model for testing cell-based therapies with human cells.

Severe combined immunodeficiency

A family of genetic disorders that affect T-cell differentiation and B-cell immunity, resulting in the absence of a functional immune system.

Ex vivo gene transfer

A gene-transfer strategy in which the target cells are removed from the individual to be treated, genetically modified in the laboratory, and then administered to the patient.

In vivo gene transfer

A gene-transfer strategy in which the vector carrying the expression cassette is administered directly to the patient.

Suicide gene

A gene that encodes a protein that can convert a non-toxic prodrug into a cytotoxic compound.

Cephalopolysyndactyly

A condition that is characterized by abnormal skull morphology and digital malformations.

First generation adenovirus vector

A gene-transfer vector that is based on adenovirus serotype 5 and is characterized by the deletion of the E1 gene, to prevent viral replication, and the E3 gene, to increase cargo space.

α1-Antitrypsin deficiency

An autosomal recessive disorder that is associated with emphysema and liver disease. It results from the deficiency of a serine protease inhibitor that is produced in the liver and secreted into the plasma, where it inhibits the activity of trypsin and elastase.

(Viral vector) serotypes

Viral vectors that belong to the same viral family, but that have sufficiently distinct capsids that they can be distinguished by differences in the antibodies that they evoke in vivo, for example, adenovirus serotypes 2 and 5 are group C Adenoviridae.

Sero-switch

A gene-transfer strategy that involves the repeated administration of alternating adenovirus vectors that are derived from different serotype subgroups, in order to circumvent anti-adenovirus humoral immunity.

Thrombocytopoenia

A persistent decrease in the number of blood platelets. It is often associated with haemorrhagic conditions.

Complement

Groups of plasma enzymes and regulatory proteins that function in innate immunity and that are activated in a cascading fashion to promote cell lysis.

Niche

A subset of tissue cells and extracellular substrates that can house one or more stem cells and control their self-renewal and progeny production in vivo.

ADA-SCID

An autosomal recessive disorder that presents in infants. The immunodeficiency results from the sensitivity of lymphocytes to the accumulation of adenosine degradation products.

X-linked SCID

A fatal immunodeficiency disorder that results from mutations in the γc-cytokine receptor. These mutations cause an early block in T and NK lymphocyte differentiation.

Thalassaemia

A group of related genetic blood disorders that result from mutations in the genes encoding either the α or β-proteins of haemoglobin, which results in anaemia of varying severity.

Dicer

A highly conserved cytoplasmic enzyme that cleaves dsRNA into small interfering RNAs.

Interferon

A family of glycoproteins that are produced and secreted by cells of the immune system to boost immune responses to viral infection.

Hammerhead ribozymes

One of the smallest ribozymes (only 30–40 nt), they are characterized by a structure consisting of three base-paired helices that are connected by two invariant single-stranded regions, which form the catalytic core.

Familial amyloidotic polyneuropathy

An autosomal dominant disorder that is characterized by deposition of amyloid fibrils in the peripheral nerves and various organs.

Retinitis pigmentosa

A retinal degeneration disease that results from one of hundreds of mutations in the rhodopsin gene. There are several varieties of this disorder, including both autosomal dominant and autosomal recessive types.

Zinc-finger nucleases

(ZFNs). Synthetic proteins that are composed of a highly specific DNA-binding domain, which comprises a string of zinc-finger motifs, and a nonspecific DNA-cleaving domain. The combination of ZFNs and DNA repair by homologous recombination represents a strategy of gene correction.

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O'Connor, T., Crystal, R. Genetic medicines: treatment strategies for hereditary disorders. Nat Rev Genet 7, 261–276 (2006). https://doi.org/10.1038/nrg1829

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