Gene therapy and genome surgery in the retina

Abstract

Precision medicine seeks to treat disease with molecular specificity. Advances in genome sequence analysis, gene delivery, and genome surgery have allowed clinician-scientists to treat genetic conditions at the level of their pathology. As a result, progress in treating retinal disease using genetic tools has advanced tremendously over the past several decades. Breakthroughs in gene delivery vectors, both viral and nonviral, have allowed the delivery of genetic payloads in preclinical models of retinal disorders and have paved the way for numerous successful clinical trials. Moreover, the adaptation of CRISPR-Cas systems for genome engineering have enabled the correction of both recessive and dominant pathogenic alleles, expanding the disease-modifying power of gene therapies. Here, we highlight the translational progress of gene therapy and genome editing of several retinal disorders, including RPE65-, CEP290-, and GUY2D-associated Leber congenital amaurosis, as well as choroideremia, achromatopsia, Mer tyrosine kinase- (MERTK-) and RPGR X-linked retinitis pigmentosa, Usher syndrome, neovascular age-related macular degeneration, X-linked retinoschisis, Stargardt disease, and Leber hereditary optic neuropathy.

Therapeutic AAV Gene Transfer to the Nervous System: A Clinical Reality

“…In hindsight, the rationale for the pursuit for therapeutic gene transfer in neurosensory disorders appears obvious: the tissue target is compartmentalized, warranting a local injection that can be positioned in close proximity to the target cells and thereby limits systemic exposure, a smaller dose requirement, and lessened safety concerns. Approaches in the retina have been on the forefront for the past two decades, resulting in Luxterna and multiple other gene therapy programs for blinding disorders currently in the clinic (reviewed by DiCarlo et al, 2018;Trapani and Auricchio, 2018). The majority of the clinical programs have been based on AAV due to its high gene transfer efficiency to retinal pigment epithelial cells and photoreceptors following a subretinal injection and the availability of many AAV variants that demonstrate altered specificity for the various retinal cell types (Vandenberghe and Auricchio, 2012).…”

“…The majority of the clinical programs have been based on AAV due to its high gene transfer efficiency to retinal pigment epithelial cells and photoreceptors following a subretinal injection and the availability of many AAV variants that demonstrate altered specificity for the various retinal cell types (Vandenberghe and Auricchio, 2012). The success and growing level of comfort around the use of AAV in the retina continues to push boundaries with the first in vivo experimental clinical trials using optogenetics and gene-editing techniques, such as CRISPR, to be targeting the retina and building on the safety and potency of AAV (DiCarlo et al, 2018).…”

Cost-effectiveness of Voretigene Neparvovec-rzyl vs Standard Care forRPE65-Mediated Inherited Retinal Disease

“…10,11 Anecdotal evidence suggests that vision improvement was maintained in some clinical trial participants followed up to 9 years after treatment 12 and persistent effects have been noted for up to 11 years in canine models. 13 A long-term benefit may be expected, as recombinant adeno-associated viruses, used as vectors in voretigene neparvovec-rzyl, "mediate long-term gene expression in the absence of an immune or inflammatory response." 14[p263]…”

Adeno-Associated Viral Gene Therapy for Inherited Retinal Disease

“…Genome-editing approaches may also be an alternative method to replace defective gene sequences (16); and where complete loss of photoreceptors has occurred, AAV-based optogenetic gene therapy to convert light-insensitive retinal neurons into artificial photoreceptors may become a viable technique for restoring vision (95). For autosomal dominant IRDs, such as Best macular dystrophy or adRP, Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR)-associated protein 9 (CRISPR-Cas9) genome surgery or gene editing might pave the way for therapeutic intervention (96,97). …”