Endogena Therapeutics, a biotech company that focuses on the first-in-class endogenous regenerative medicines, just announced treating the first patient with their lead product — small molecule for a photoreceptor regeneration. This step marked the beginning of a phase 1/2a clinical study for the novel treatment approach for retinitis pigmentosa, a genetic degenerative disease which leads to blindness.
Retinitis pigmentosa (RP) is a group of inherited diseases affecting 1 in 3,000-7,000 people, causing slow and progressive retinal degeneration, which finally can lead to the full loss of vision. “Inherited” hints that RP is caused by defective genes, which can have one of three inheritence patterns. The most common one is autosomal dominant, when one copy of an altered gene is enough to cause the disorder. The autosomal recessive inheritance is characterized by the pattern in which two gene copies should carry the mutation for the RP phenotype. Last, but not the least, in the X-linked inheritance the mutated gene is located on the X-chromosome, hence all men with the mutated gene will develop RP; females usually need two defective gene copies to develop RP, but around 20% have clinical symptoms even with one alteration.There are few other inheritance patterns described for RP, but they are comparatively rare.
So far, there are more than 80 genes identified, alterations in which lead to syndromic and non-syndromic RP, indicating the considerable level of disease heterogeneity. The function of these mutated genes involve phototransduction, photoreceptor development, retinal homeostasis and many more.
Considering that the genetic mechanisms for the majority of RP types were discovered, it became the central strategy in building the therapeutic approaches to fight the disease. Firstly, when the altered gene is identified, gene therapy can be applied to deliver a correct copy of the gene directly to the retina cells, usually using viral vectors (“carriers”). This approach was used for Luxturna — the first FDA-approved gene therapy for RP. Patients can be treated with Luxturna if they have autosomal recessive mutations in RPE65, the gene which codes the essential protein in the visual cycle of the retina. The approval of Luxturna induced an intensive research in the direction of gene therapy for RP, resulting in multiple other candidates entering the clinical trials.
Several other approaches in developing the RP treatment involve antisense RNA oligonucleotides (AONs) and stem cells replacement. In the first case, the therapy is also gene-specific, but unlike gene therapy where the “correct” DNA sequences are delivered into the cells, AONs are short RNA molecules binding the “incorrect” RNAs preventing them from being translated into the mutant protein. This strategy is suitable for autosomal dominant inheritance pattern, since when the product from the dominant altered gene is blocked, the correct protein can be produced from the recessive correct gene copy. For example, AONs were used in the RP treatment development when RHO gene is mutated (which codes rhodopsin — the main protein of functioning rod cells).
On the other hand, stem cells replacement is a gene-independent treatment and involves mainly the transplantation of induced stem or progenitor cells into the retina, which then can regenerate the layer of functioning retinocytes. The general approach involving stem and progenitor cells is also widely used for other degenerative diseases, like age-related muscle degeneration.
Endogena Therapeutics developed a novel small-molecule approach (EA-2353) that selectively activates endogenous retinal stem and progenitor cells, which differentiate into photoreceptors and can hence potentially preserve or restore visual function. This gene-independent treatment approach has some advantages in RP, which has multiple genetic causes.
The Endogena’s approach was granted orphan drug designation by the U.S. Food and Drug Administration in May 2021. The phase 1/2a dose-escalation study will examine the safety, tolerability and the preliminary efficacy of EA-2353 administered by intravitreal injection. A total of 14 patients with RP due to any pathologic genetic mutation will be recruited across up to six sites in the USA.
Principal Investigator, Mark Pennesi, MD, PhD, Professor of Ophthalmology at the Casey Eye Institute in Oregon, USA, said: “This is very exciting and I am hopeful that this new treatment has the potential to be a major game-changer for patients with RP who currently have no other options”.
Endogena’s artificial intelligence-driven drug discovery platform, combined with knowledge of molecular pathways that regulate retinal stem cells and retinal pigment epithelial cells, provides a potential new treatment paradigm to tackle degenerative conditions related to aging and genetic disorders. Beyond EA-2353, other products in Endogena’s pipeline include a treatment for dry age-related macular degeneration (AMD), which is approaching IND-enabling studies.
Overall, implementing a gene-dependent treatment for RP is both advantageous and restrictive. On one hand, the exact cause of the disease can be targeted and “fixed”, which produces a stable result of the expected and easier-to-predict character, but the other side of the coin is darkened with the limitation by the certain gene which is targeted. This means that each gene out of more than 80 known RP-associated genes requires a different type of treatment. Regardless of such a limitation, Luxturna treatment by Spark Therapeutics is an example of successful approval and a hope for at least some RP patients. Multiple other companies are also developing gene therapy for RP, like GenSight Biologics and 4D Molecular Therapeutics. Both companies had their RP gene therapies granted with the FDA Fast Track Designation, and the clinical studies are ongoing.
On the other hand, a stem and progenitor cells transplantation is a more expensive treatment with less controlled results, which also requires careful safety considerations, but it can be theoretically applied for all the patients with RP. This cell therapy strategy was used by the UK-based company ReNeuron, which entered clinical trials with its human retinal progenitor cells (hRPC) treatment. Even though the treatment was promising, this year they announced the termination of the clinical trial process due to the contradictory results in the Phase 2a and the lack of hRPC treatment efficiency. At the same time, jCyte also used a strategy involving retinal progenitor cell injections, and their Phase 2b clinical trials showed some significant improvements for the RP patients treated with their cell therapy. Currently jCyte is planning to enter a Phase 3 clinical trial.
The small-molecule treatment by Endogena Therapeutics is a new approach, which could benefit all the types of RP if it gets approved. It has an advantage of inducing the endogenous retinal stem and progenitor cells, compared to the transplantation approach, however since Endogena just entered the clinical trials with this treatment it requires further careful investigation, the results of which are hard to predict. The estimated study completion date is scheduled for the end of 2023, which will give more insights into the tolerability and efficiency of the new RP treatment.
Topics: Novel Therapeutics