Scholars

Haiyan Zhou, MD, PhD

University College London

Disease Areas

Rare / Orphan, Neuroscience

Focus

Nucleic Acid Therapy to Treat Loss of Sensation and Neuropathic Pain Caused by a Rare Genetic Defect

Scholar Profile

2024 Oxford-Harrington Rare Disease Scholar

Hereditary sensory and autonomic neuropathy type 1, or HSN1A, is a progressively debilitating disorder typically starting in late teen or young adult years. Patients lose the ability to feel physical sensations properly, leading to unbearable shooting pain, numbness, skin ulcers, and in the more severe cases, requiring amputation. No effective treatment exists. Dr. Zhou is focused on developing an antisense oligonucleotide (ASO)-based genetic therapy to treat HSN1A.

The disorder has been traced to the Serine Palmitoyl Transferase Long Chain base subunit 1 (SPTLC1) gene, which provides instructions for serine metabolism and production of sphingolipids, essential for brain and nerve functioning. Genetic defects in SPTLC1 change the enzyme function in that metabolic process, resulting in a buildup of neurotoxic metabolites that eventually lead to nerve damage.

A big challenge in ASO development is to identify the most efficacious and safest product in appropriate modeling systems for translation to patients. Dr. Zhou is excited about the results of testing in mice, human skin cultures, and human-derived neurons that support her approach.

“In the humanized mouse models, we achieved exciting and promising therapeutic outcomes as measured in various affected organs, without affecting the wild-type transcripts,” Dr. Zhou says. “Our data provided the first proof-of-concept for ASO-mediated mutant allele-specific silencing for the treatment of SPTLC1- related HSN1. Now we are testing our lead ASO candidates for further studies on efficacy and safety, towards the clinical translation.”

More than 70 adults and 100 children in the United Kingdom are affected by SPTLC1-HSN1A. Other cases exist in Canada, Australia, and the United States.

"The ASO strategy has potential for other peripheral nervous system disorders."