Gene Therapy in Ophthalmology: Promise and Pragmatism

Abstract

The aim of gene therapy is long lasting improvement or sure of a certain disease by transfer of genetic material to the patient. It may involve either of gene replacement, gene slicing, gene editing or addition.¹ Over the years, gene therapy has been extensively in practice with the use of adeno-associated virus (AAV) vectors for gene delivery and has been applied to neurodegenerative disease, cardiovascular disease, cancers and ocular disease.²

Eye is an excellent organ for gene vector delivery due to its immune privilege and direct visibility.³ In 2017, ‘’Voretigene Neparvovec’’ was the first gene vector to be approved by Food and Drug administration (FDA) for the treatment of RPE65 related inherited retinal dystrophy. Gene vector can be introduced into the eye by sub retinal injection after pars plana vitrectomy, intravitreal or suprachoroidal injections.⁴

Autosomal dominant retinitis pigmentosa (ADRP) is the most prevalent form of this disease and rhodopsin P23H (RHO-P23H) being the frequent mutant gene locus. Yan et al. developed sgRNA to specifically target the mutated rhodopsin RHO-P23H, subsequently resulting in knockdown in an ADRP mouse model induced by RHO-P23H mutation.⁵ Choroideremia is an X linked recessive disorder due to mutations in CHM gene.  Five clinical trials have been conducted on gene therapy for this disease with the first commencing in 2011. Adeno assisted virus vector (AAV) was introduced in subject’s eyes after pars plana vitrectomy. Different strengths of AAV were used in these five trials. At 1 year, minimum gain of ETDRS letters was 2 while maximum gain was 17 letters in one of the trials. Only one patient diagnosed to have retinal tractions and stretching.^{6, 7}