Curative gene therapies for rare diseases

Abstract

Diseases caused by alterations in the DNA can be overcome by providing the cells or tissues with a functional copy of the mutated gene. The most common form of gene therapy implies adding an extra genetic unit into the cell. However, new genome engineering techniques also allow the modification or correction of the existing allele, providing new possibilities, especially for dominant diseases. Gene therapies have been tested for 30 years in thousands of clinical trials, but presently, we have only three authorised gene therapy products for the treatment of inherited diseases in European Union. Here, we describe the gene therapy alternatives already on the market in the European Union and expand the scope to some clinical trials. Additionally, we discuss the ethical and regulatory issues raised by the development of these new kinds of therapies.

Keywords: CRISPR-Cas9; Gene therapy; Genetic engineering.

Fig. 1

Flow chart model of biological and technical variables describing gene therapy strategies. (a) Type of disease mutation. Loss-of-function mutations can be treated by supplying the cells with a functional copy of the gene in the form of DNA or mRNA. If the disease-causing mutation results in gain-of-function or dominant-negative product, the current alternatives imply correcting the alteration or excising the altered allele using gene-editing tools (ZFN, TALEN, CRISPR/Cas9). (b) The affected tissue type has a major influence whether the disease can be targeted using in vivo or ex vivo therapies. Self-renewing tissues are much more approachable with ex vivo treatments. (c) Delivery options are determined by the tissue type and approach. Viral particles can be used both in vivo and ex vivo. Chemical or physical means are mainly used in ex vivo therapies. Created with BioRender.com