Mitigation of Nuclear Pore defect in Neurodegeneration: ESCRT Pathway Inhibition

Value Proposition

• Novel Target: CHMP7, a nuclear pore protein, identified as a key driver in ALS, offers a new therapeutic approach.
• Disease-Modifying Method: Targets the root cause of nuclear pore complex injury and neural injury, aiming to alter disease progression.
• Druggable Target: CHMP7 can be inhibited using small molecule, gene, and peptide therapies.
• Broad Impact: Potential to treat multiple neurodegenerative diseases

Unmet Need

Neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS) often involve disruptions in nucleocytoplasmic transport essential cellular processes for maintaining survival and function. While many studies have suggested that specific nucleoporins (Nups) are mislocalized in these diseases, the exact mechanisms of nuclear pore complex (NPC) injury and the resulting cellular consequences have remained unclear. There is an unmet need to identify and target the mechanisms driving NPC injury to develop effective therapies for ALS and other neurodegenerative diseases.

Technology Description

 Johns Hopkins researchers have identified the ESCRT-III pathway, specifically mediated byCHMP7, as a key contributor to NPC injury in C9orf72 ALS. This novel discovery reveals that the aberrant activation of CHMP7 leads to the degradation of specific Nups, resulting in disruptions in NCT and contributing to neuronal death. Their work demonstrates that by targeting CHMP7, it is possible to mitigate these disruptions and potentially halt disease progression. Preliminary data indicate that CHMP7 knockdown in induced pluripotent stem cell-derived neurons (iPSNs) effectively prevents the loss of Nups, highlighting its therapeutic potential.

Stage of Development

• Pre-clinical

Data Availability: In vitro and clinical data

Looking for Partners to:

Develop and commercialize as a disease-modifying therapy for ALS, with potential applications in other neurodegenerative diseases characterized by NPC injury. This technology is available non-exclusively.

Publication

• Alyssa N. Coyne et al. Sci. Transl.Med 13,eabe1923 (2021). DOI:10.1126/scitranslmed.abe1923.