Casma to develop CSM-101 as treatment for Parkinson’s
Oral therapy will also target Gaucher disease, company says
Casma Therapeutics said it will develop CSM-101 as a potential disease-modifying oral treatment for people with Parkinson’s disease and Gaucher disease.
CSM-101 is a first-in-class small molecule designed to activate the calcium channel TRPML1, a key regulator of lysosomal function and autophagy, a process in which cells deliver waste to cellular structures called lysosomes to be broken down and recycled. Boosting autophagy is aimed at reducing the toxic buildup of molecules that are thought to drive the development of Gaucher’s and Parkinson’s.
“Our nomination of CSM-101 marks a major milestone for Casma and the field as we translate our deep expertise in autophagy and lysosomal biology into therapeutic candidates,” Frank Gentile, PhD, CEO of Casma, said in a company press release.
Based on favorable preclinical data, the company plans to submit an investigational new drug (IND) application to the U.S. Food and Drug Administration seeking permission to test CSM-101 in patients starting in the first half of 2026.
The GBA1 gene encodes beta-glucocerebrosidase (GCase), an enzyme essential for the function of lysosomes. Mutations in the GBA1 lead to a faulty GCase, which means molecules that should have been degraded build up to toxic levels inside cells. In Gaucher’s, a faulty GCase causes the buildup of fat-like lipid molecules in organs and tissues.
Treatment targets ‘central driver of disease progression’
GBA1 mutations are also known to raise the risk of Parkinson’s by up to about 20 times, and patients with this genetic defect often develop symptoms sooner and progress faster. In these patients, lysosome dysfunction triggers the buildup of toxic alpha-synuclein protein, which is thought to drive nerve cell damage that gives rise to the hallmark motor symptoms of Parkinson’s.
CSM-101 is an orally available small molecule designed to restore lysosomal function by activating TRPML1, a critical lysosome channel protein. Lysosomes are cellular structures that act like recycling centers, breaking down waste, damaged parts, and unwanted materials inside the cell. A $370,000 grant from the Michael J. Fox Foundation for Parkinson’s Research supported Casma’s development of TRPML1 activators for Parkinson’s.
“CSM-101 represents a scientifically validated and targeted approach to restoring lysosomal function through TRPML1 activation, addressing a central driver of disease progression in Gaucher’s disease and Parkinson’s disease,” said Leon Murphy, PhD, Casma’s chief scientific officer.
The company plans to develop CSM-101 first for Gaucher’s patients with Parkinson’s, potentially expanding into GBA-associated Parkinson’s and idiopathic Parkinson’s, or Parkinson’s stemming from unknown cause.
“By focusing first on genetically defined patient populations and leveraging robust biomarkers, we are positioned to deliver rapid clinical proof of concept with the potential for meaningful benefits for patients,” Murphy said.
In preclinical studies, CSM-101 was able to access the brain and spinal cord, where it significantly reduced toxic lipid levels and neuroinflammation and extended survival in multiple Gaucher’s models. In models of GBA-related Parkinson’s and idiopathic Parkinson’s, CSM-101 lowered toxic alpha-synuclein levels and preserved nerve cells.
These findings, combined with favorable safety and pharmacological data, provide a strong rationale for CSM-101’s clinical development as a potential disease-modifying therapy for Gaucher’s and Parkinson’s, per Casma.
“Our preclinical data demonstrate that activating TRPML1 effectively addresses lysosomal dysfunction, a central driver in both rare and prevalent neurodegenerative diseases,” Gentile said.
Casma presented the preclinical data supporting the CSM-101’s development into IND-enabling studies at the GBA1 Meeting 2025, held June 5-7 in Montreal.
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