Gene Therapy for Inherited Retinal Disorders: Update on Clinical Trials

Abstract

Within the last decade, continuous advances in molecular biological techniques have made it possible to develop causative therapies for inherited retinal disorders (IRDs). Some of the most promising options are gene-specific approaches using adeno-associated virus-based vectors to express a healthy copy of the disease-causing gene in affected cells of a patient. This concept of gene supplementation therapy is already advocated for the treatment of retinal dystrophy in RPE65-linked Leberʼs congenital amaurosis (LCA) patients. While the concept of gene supplementation therapy can be applied to treat autosomal recessive and X-linked forms of IRD, it is not sufficient for autosomal dominant IRDs, where the pathogenic gene product needs to be removed. Therefore, for autosomal dominant IRDs, alternative approaches that utilize CRISPR/Cas9 or antisense oligonucleotides to edit or deplete the mutant allele or gene product are needed. In recent years, research retinal gene therapy has intensified and promising approaches for various forms of IRD are currently in preclinical and clinical development. This review article provides an overview of current clinical trials for the treatment of IRDs.

mRNA trans-splicing dual AAV vectors for (epi)genome editing and gene therapy

“…Next, we analyzed the performance of REVeRT in a dual AAV vector setting in vivo. The retina is the target organ of one of the first approved AAV gene therapies and for many others currently in clinical development 26 , 27 . However, more than 30 inherited retinal disorders are caused by mutations in large genes exceeding the AAV vector DNA capacity ( https://sph.uth.edu/retnet/ ).…”

mRNA trans-splicing dual AAV vectors for (epi)genome editing and gene therapy

“…Next, we analyzed the performance of REVeRT in a dual AAV vector setting in vivo . The retina is the target organ of one of the first approved AAV gene therapies and for many others currently in clinical development 25, 26 . However, more than 30 inherited retinal disorders are caused by mutations in large genes exceeding the AAV vector DNA capacity (https://sph.uth.edu/retnet/).…”

Choosing Outcome Measures and Assessing Efficacy of Therapeutic Interventions in Inherited Retinal Diseases: The Importance of Natural History Studies

“…1,2 Numerous other gene-specific and mutation-specific trials are in progress, including several ones that have already reached Phase 3. [3][4][5] IRDs, however, have proven to be far more genetically heterogeneous than initially predicted. Thus, the field of IRDs is faced with the daunting task of developing hundreds of distinct gene-specific treatments and an even larger number of mutation-specific therapies.…”

“…In 2017, the Food and Drug Administration (FDA) has approved the first ever IRD gene therapy, voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics/Roche) 1,2. Numerous other gene-specific and mutation-specific trials are in progress, including several ones that have already reached Phase 3 3–5…”