Gene therapy for inherited retinal diseases: progress and possibilities

ABSTRACT

Inherited retinal diseases (IRDs) comprise a heterogeneous group of genetic disorders affecting the retina. Caused by mutations in over 300 genes, IRDs result in visual impairment due to dysfunction and degeneration of photoreceptors, retinal pigment epithelium, or the choroid. Important photoreceptor IRDs include retinitis pigmentosa and Leber congenital amaurosis. Macular dystrophies include Stargardt and Best disease. Currently, IRDs are largely incurable but the landscape of treatment options is rapidly changing for these diseases which, untreated, result in severe visual impairment and blindness.

Advances in DNA delivery to the retina and improved genetic diagnosis of IRDs have led to a new era of research into gene therapy for these vision-threatening disorders. Gene therapy is a compelling approach due to the monogenic nature of most IRDs, with the retina being a favourable target for administering genetic vectors due to its immunoprivileged environment, direct visibility, and multiple methods to assess sensitivity and function. Generally, retinal gene therapy involves a subretinal or intravitreal injection of a viral vector, which infects target cells to deliver a therapeutic gene, or transgene. A gene augmentation strategy introduces a functioning copy of a gene to restore expression of a mutated gene, whereas a gene-editing strategy aims to directly edit and correct the mutation. Common delivery vectors include adeno-associated virus (AAV) and lentivirus.

Voretigene neparvovec-rzyl (Luxturna) became the first FDA-approved direct gene therapy in December 2017, and the Australian TGA followed suit in August 2020. More are projected to follow, with clinical trials underway for many other IRDs.

This review provides an overview of gene therapy for IRDs, including current progress and challenges. A companion article in this issue details target patient populations for IRD gene therapy, and how optometrists can assist in assessing individuals who may be eligible for current and future therapies.

KEYWORDS:

• Gene therapy
• inherited retinal disease
• retinitis pigmentosa
• genetic vector

Key messages

• Gene therapy is a safe and effective treatment that is now becoming available for patients with inherited retinal diseases, which were previously untreatable.

• Various strategies exist to target the many different genetic mutations that result in retinal pathology, and have demonstrated efficacy in clinical trials.

• Luxturna, for RPE65-associated Leber congenital amaurosis, was the first retinal gene therapy drug to be commercially approved, representing a landmark in gene therapy to treat ocular conditions. More are projected to follow.

• The success of retinal gene therapy depends on the accurate diagnosis (phenotype and genotype) of patients suspected to have inherited retinal diseases.

Glossary

• Autosomal dominant: pattern of inheritance where only one affected copy of the gene is sufficient to cause disease

• Autosomal recessive: pattern of inheritance where both copies of the gene must be affected to cause disease

• Capsid: the protein shell of a virus

• Biallelic: referring to both alleles of a gene carried by an individual

• Ex vivo: taking place outside the body

• Genome: the genetic material of an organism

• In vivo: taking place within the body

• kb: kilobase – 1000 bases of a nucleic acid (DNA or RNA)

• Nucleotide: a building block of DNA (consisting of deoxyribose nucleotides) or RNA (consisting of ribose nucleotides)

• Recombinant: of genetic material; created from multiple sources

• Serotype: a virus strain that does not cross-react with neutralising antibodies specific for other virus strains

• Transduction: introduction of DNA into a target cell by a viral vector

• Transgene: a therapeutic gene introduced into a target cell

• Tropism: ability of a virus to infect different cell types

• Vector: vehicle used to carry genetic material to the desired target

Disclosure statement

No potential conflict of interest was reported by the authors.