Clinical development of gene therapy: results and lessons from recent successes

Abstract

Therapeutic gene transfer holds the promise of providing lasting therapies and even cures for diseases that were previously untreatable or for which only temporary or suboptimal treatments were available. For some time, clinical gene therapy was characterized by some impressive but rare examples of successes and also several setbacks. However, effective and long-lasting treatments are now being reported from gene therapy trials at an increasing pace. Positive outcomes have been documented for a wide range of genetic diseases (including hematological, immunological, ocular, and neurodegenerative and metabolic disorders) and several types of cancer. Examples include restoration of vision in blind patients, eradication of blood cancers for which all other treatments had failed, correction of hemoglobinopathies and coagulation factor deficiencies, and restoration of the immune system in children born with primary immune deficiency. To date, about 2,000 clinical trials for various diseases have occurred or are in progress, and many more are in the pipeline. Multiple clinical studies reported successful treatments of pediatric patients. Design of gene therapy vectors and their clinical development are advancing rapidly. This article reviews some of the major successes in clinical gene therapy of recent years.

Figure 1

In vivo versus ex vivo gene therapies for the treatment of genetic diseases and cancer. In vivo gene therapy involves direct introduction of vector (carrying the therapeutic gene) into the patient (either into or near the target organ). This strategy has achieved success in the treatment of eye diseases, neurological disorders, and hemophilia In ex vivo gene therapy, a patient’s cells (e.g., hematopoietic cells) are taken out of the body and then transduced by a vector in culture to incorporate the therapeutic gene. Finally, the gene-modified cells are transplanted back to the patient. Various inherited metabolic and immunological disorders and different types of cancers have been successfully treated with ex vivo gene therapy. AADC, aromatic L-amino acid decarboxylase; ADA-SCID, adenosine deaminase severe combined immunodeficiency; ALL, acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia; LCA II, Leber’s congenital amaurosis II; LHON, Leber’s hereditary optic neuropathy; MLD, metachromatic leukodystrophy; SCID-X1, X-linked severe combined immunodeficiency; WAS, Wiskott-aldrich syndrome.

Figure 2

Schematic illustration of two viral vectors widely used in clinical gene therapy. (a) Adeno-associated viral (AAV) vectors are prevalently used for in vivo gene therapy. Given the many serotypes and capsid variants that have been developed, these vectors can target a wide variety of tissues but are limited by their transgene carrying capacity (~5 kb for single-stranded, ssAAV, and 2.5–3 kb for self-complementary, scAAV). (b) Lentiviral vectors (LV) can carry up to 8 kb of transgene and are used in many ex vivo gene therapy protocols, in particular for HSC gene transfer. LV can be pseudotyped with envelopes from different viruses and thereby adapted to a broad range of targets. cPPT, central polypurine tract; LTR, long terminal repeat; Ψ: Packaging signal; RRE, Rev responsive elements; SIN LTR, self-inactivating LTR (with partial deletion in U3 region of 3’LTR); WPRE, Woodchuck hepatitis viral post-transcriptional regulatory element.