PYC-001: A Promising RNA Therapeutic for Autosomal Dominant Optic Atrophy

Abstract

Purpose : This investigation aims to evaluate the efficacy of PYC-001, a cell-penetrating peptide-antisense oligomer conjugate targeting the Optic atrophy 1 (OPA1) mRNA, as a potential therapeutic intervention for Autosomal Dominant Optic Atrophy (ADOA). One of the most persistent challenges in treating inherited retinal diseases has been the efficient delivery of drugs into target cells. PYC-001's distinctive design specifically overcomes this challenge by improving drug delivery to the crucial retinal ganglion cells (RGCs) central to ADOA pathogenesis, presenting a potential solution for associated challenges in the condition.

Methods : PYC-001 was designed to target translational inhibitory elements within the 5’UTR of OPA1 mRNA to enhance protein translational efficiency. The capability of PYC-001 to elevate OPA1 protein levels and alleviate cellular abnormalities associated with ADOA was assessed using iPSC-RGCs obtained from ADOA patients. To assess the delivery and target engagement of PYC-001 in specific cells, it was administered via intravitreal injection in rabbit and non-human primate models.

Results : PYC-001 exhibited the capacity to increase OPA1 protein levels in iPSC-RGCs derived from three ADOA patients, each with distinct OPA1 mutations. The upregulation reached up to 1.4-fold, making it close to that observed in the healthy range within cell types representing those primarily affected in ADOA disease. This enhancement comprehensively restored the mitochondrial network. In addition, concomitant increased production of cellular bioenergetics as determined using an oxygen consumption rate assay, was observed across the range of explored OPA1 mutations.

PYC-001's unique cell-penetrating characteristics enable superior delivery to RGCs, rendering it a promising treatment avenue for ADOA. PYC-001 reached the neural retina, specifically targeting the RGC layer following a single intravitreal injection in both rabbits and non-human primates. In non-human primates, a safe dosage of PYC-001 led to a 1.6-fold increase in OPA1 protein within the RGC layer proximal to the optic nerve head, indicating substantial uptake in models with physiological relevance to humans.

Conclusions : PYC-001 is progressing in IND-enabling studies toward anticipated clinical trials slated for commencement in 2024. This ongoing investigation highlights the potential of PYC-001 as a promising treatment avenue for unmet medical needs in ADOA.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.