EyeDNA Therapeutics Reports Positive 24-Month Data for HORA-PDE6b Gene Therapy in Retinitis Pigmentosa Trial

Neurodegenerative diseases are often characterized by the misfolding and accumulation of specific proteins, which lead to neuronal damage and disease progression. For instance, beta-amyloid and tau are associated with Alzheimer’s disease, alpha-synuclein with Parkinson’s disease and related disorders, mutated huntingtin with Huntington’s disease, and TAR DNA-binding protein 43 (TDP-43) with Amyotrophic Lateral Sclerosis (ALS). The presence of TDP-43 proteinopathy, which involves the abnormal accumulation of misfolded TDP-43 in the cytoplasm, is a key feature of ALS and other neurodegenerative conditions. The mechanisms behind TDP-43 proteinopathies are believed to include disruptions in the balance of nuclear-cytoplasmic protein localization, aggregation of ubiquitinated and hyper-phosphorylated TDP-43, and increased truncation of cytoplasmic TDP-43.

In synucleinopathies, such as Parkinson’s disease, Dementia with Lewy bodies, and Multiple System Atrophy, the pathological hallmark is the accumulation of alpha-synuclein (aSyn), which forms neuronal and glial inclusions that are misfolded, phosphorylated, and insoluble.

Over the past ten years, various treatment strategies targeting protein aggregates have been explored in both preclinical and clinical studies. For ALS, these strategies include biologics and small molecules aimed at addressing TDP-43 pathology. In Parkinson’s disease, approaches range from passive or active immunization to remove aggregated aSyn, to the use of vectorized antibodies, small molecule anti-aggregants, and methods to lower aSyn gene expression.

The autophagy lysosomal pathway (ALP) plays a crucial role in degrading toxic protein aggregates within cells. Key components of the ALP, such as Glucocerebrosidase (GBA1) and Transcription Factor EB (TFEB), are integral to the clearance of protein aggregates. Coave Therapeutics, a clinical-stage biotechnology company, is developing gene therapies for rare ocular and CNS diseases. Utilizing their ALIGATER™ platform, they have created a coAAV-based genetic medicine approach to deliver GBA1 and TFEB to specific CNS structures, with the goal of activating or restoring autophagy and lysosomal functions. This approach aims to eliminate or prevent the accumulation of toxic protein aggregates associated with neurodegenerative diseases.

The company's focus on enhancing the ALP's role in clearing protein aggregates represents a novel therapeutic strategy for neurodegenerative diseases. By targeting the underlying cellular mechanisms that contribute to protein misfolding and aggregation, Coave Therapeutics is pioneering a new frontier in the treatment of these debilitating conditions.