Gene therapy approaches include gene addition, gene knockdown and gene alteration/correction.
Gene transfer vectors involve the use of non-viral DNA plasmids or are derived from the modification of natural viruses.
Vectors can be designed to express therapeutic protein coding and/or non-coding RNAs. Therapeutic non-coding RNAs include RNAi and microRNAs.
Improvements in gene transfer vector technologies are responsible for early clinical successes in treated inherited blindness, immunodeficiency syndromes and a neurodegenerative disease.
Some technical barriers still exist that limit the wide-scale implementation of gene therapy.
Improved vectors and a better understanding of vector–host interactions are two of the most important goals of gene therapy research.
The advancement in disease prediction using personalized genomics will ultimately influence the use of gene transfer in preventative medical applications.
Improvements in the gene transfer vectors used in therapeutic trials have led to substantial clinical successes in patients with serious genetic conditions, such as immunodeficiency syndromes, blindness and some cancer types. Several barriers need to be overcome before this type of therapy becomes a widely accepted treatment for a broad group of medical diseases. However, recent progress in the field is finally realizing some of the promises made more than 20 years ago, providing optimism for additional successes in the near future.
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I would like to thank my previous mentors, past and current trainees, and colleagues for all they have taught me. I apologize for not being able to include many other important approaches and studies owing to a lack of space. This work was funded by grants from the US National Institutes of Health (National Heart, Lung and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, and National Institute of Allergy and Infectious Diseases) and the Juvenile Diabetes Research Foundation.
The author declares no competing financial interests.
- Zinc finger nucleases
Engineered DNA-binding proteins that produce double-strand breaks at specific sequences. They can be used to correct or induce mutations in genomic DNA.
(RNA interference). The process by which the introduction or expression within cells of dsRNA leads to the sequence-specific cleavage and degradation of a target mRNA and therefore to gene suppression.
- miRNA sponges
Exogenously delivered or expressed non-coding RNAs that bind and inhibit microRNA function in a sequence-specific manner.
- RNA aptamers
Short RNAs selected from large libraries that, owing to their three-dimensional structure, bind to and activate or interfere with protein function and/or direct a macromolecular cargo (for example, small interfering RNAs) into cells via a targeted receptor.
The use of an unnatural or unmatched envelope or capsid protein to package a viral genome.
- Severe combined immune deficiency
(SCID). A lethal disease caused by the lack of B cell and T cell immunity. The disease is caused by a deficiency of one of several genes. It is commonly referred to as the 'bubble boy' disease.
- X-linked adrenoleukodystrophy
An X-linked, neonatal, neuronal de-myelinating disorder.
- RNA decoys
RNA molecules designed to bind and inhibit a biologically active RNA from binding to its target.
- Epidermolysis bullosa
An inherited connective tissue disease resulting in mild to severe (fatal) skin blisters owing to a mutation in collagen or keratin genes.
- Self-limiting toxicity
A toxicity reaction that resolves without intervention.
- Ornithine transcarbamylase deficiency
Ornithine transcarbamylase is an enzyme in the urea cycle that is crucial for the conversion of ammonia to urea. Deficiency results in high blood ammonia levels, mental retardation and possible death.
- Helper-dependent packaging system
A means of packaging adenoviral vectors that are devoid of all their genes. The pared-down adenoviral genome is expressed from a helper adenovirus that lacks a packaging signal; this permits the vector but not the helper virus to be packaged.
- Leber's congenital amaurosis
An inherited and incurable blindness disorder.
- Ambulatory vision
The degree of vision that allows one to see enough to get around a room without bumping into objects.
- Image-guided vector placement
The use of imaging technologies, such as real-time magnetic resonance imaging, to pinpoint the delivery of a vector through a catheter.
- Minicircle DNAs
Expression cassettes that are devoid of the plasmid DNA backbone.
- Sleeping Beauty
An ancient inactive transposon isolated from salmon. The transposase was reactivated by introducing various mutations.
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Kay, M. State-of-the-art gene-based therapies: the road ahead. Nat Rev Genet 12, 316–328 (2011). https://doi.org/10.1038/nrg2971
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