Although rare diseases are individually rare, around the globe nearly 400 million people suffer from approximately 7,000 different rare diseases. Approximately 80% of all rare diseases are genetic in origin, and most of these diseases are monogenic, i.e., follow one gene – one disorder pattern of inheritance. Despite showing monogenic inheritance patterns, the genetic etiology of around half of all these diseases remains unknown. Even in cases of known genetic etiology, the diseases can display variable phenotypes with the same mutation. Conversely, some people with known disease-associated genetic mutations may report no disease presentation. Genetic mutations may not have a linear association with disease phenotypes making it difficult to identify the genetic origins of a specific phenotype.
Modifier genes can increase or decrease the severity of the phenotypic outcome of the disease but may not be disease-causing themselves. The direct impact of genetic modifiers has been studied extensively in several diseases including cystic fibrosis, epileptic encephalopathy, spinocerebellar ataxia type 1, spinal muscular atrophy, dystonia, and retinal degeneration. These diseases show drastically altered phenotypes with changes in the modifier gene variants. Master regulators of transcription, such as nuclear hormone receptors, are particularly interesting since they modulate numerous key biological networks essential for maintaining retinal homeostasis.
Inherited retinal dystrophies (IRDs) are a heterogeneous set of visual impairment symptoms due to pathogenic mutations in at least 317 nuclear and mitochondrial genes or gene loci. IRDs affect various retinal areas and impair vision in affected individuals but the genetic interpretation is difficult because of the lack of distinct genotype-phenotype correlations of IRD-causing genes, different inheritance patterns, presence of hypomorphic alleles, and modifier genes. The discovery of novel pathogenic mutations in IRD-related genes has substantially improved from advances in bioinformatics and next-generation sequencing. IRDs can be classified as non-syndromic (retinitis pigmentosa, Leber congenital amaurosis, cone/cone-rod dystrophy, Stargardt disease, and congenital stationary night blindness) and syndromic (Alström syndrome, Bardet-Biedl syndrome, Joubert syndrome, Senior-Loken syndrome, and Usher syndrome). Although retinitis pigmentosa (RP) accounts for the majority of IRDs, about 40% of RP patients cannot be genetically diagnosed, confounding the ability to develop personalized RP therapies.
Developing individualized gene therapy for rare diseases is challenging due to the large mutational diversity and the lack of a definitive genetic etiology which limits the potential benefit of gene augmentation therapy. Modifier genes such as the nuclear hormone receptors (NHRs) are master regulators of multiple molecular pathways and restore cellular homeostasis. Therefore, a single modifier gene therapy could reverse the pathological phenotypes of IRDs with multiple gene mutations.
Nr2e3, an NHR was tested by Haider et al, as a modifier gene therapy in five different genetic mouse models of RP (FVB-Pde6β rd1/NJ (rd1), Rhodopsin null allele (Rho−/−), B6.129S6(Cg)-Rhotm1.1Kpal/J (RhoP23H), BXD24/TyJ-Cep290rd16/J (rd16) and Nr2e3rd7/J (rd7)). The study reported that Nr2e3 improved the phenotype and retinal function in all five genetic mouse models through the regulation of several key biological networks that are critical to maintaining retinal homeostasis in the retina including phototransduction, cell survival, apoptosis, immunity, oxidative stress, ER stress, neuroprotection, and metabolism.
Currently, there is only FDA-approved gene augmentation therapy for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy called Leber congenital amaurosis type 2 (LCA2). This treatment delivers the normal RPE65 copy into retinal cells restoring the normal visual cycle and thereby improving vision. However, LCA affects 1 in 80,000 individuals with RPE65 only accounting for 6% of all LCA cases (≈250 cases in the United States). Within the United States, an estimated 200,000–300,000 people are affected by an IRD, which projects a worldwide prevalence estimate of two million. The economics and scientific effort of correcting over 317 genes and gene loci involved in different IRD phenotypes and severity, by gene augmentation therapy would be monumental because this approach may require development of hundreds of products to address the needs of these patients. Therefore, a gene-agnostic approach like modifier gene therapy might allow for more efficient therapy with a greater potential to reach many of these patients who are in a desperate need of rescue from blindness. Using a modifier gene therapy approach, Ocugen is currently conducting a Phase 1/2 clinical trial of OCU400 (AAV5-hNR2E3) in retinitis pigmentosa patients with NR2E3 and RHO gene mutations and in LCA patients with CEP290 gene mutations. To learn more, about Ocugen’s modifier gene therapy approach, visit the Ocugen website. To receive more information about the OCU400 Phase 1/2 study, please contact Ocugen at [email protected] or call 484-237-3384.