(i) To develop a brain-penetrant small molecule agonist for the lysosomal TRPML1 channel and, (ii) Perform preclinical studies supporting development in Parkinson’s-related disorders.

Lysosomal homeostasis is critical for metabolism of certain proteins and lipids which would otherwise accumulate leading to cellular stress and pathologies. Alterations in the endolysosomal pathway are common in Parkinson’s disease (PD) and related disorders such as Gaucher’s disease (GD). Heterozygous mutations in GBA1, which encodes the lysosomal enzyme GCase, are reported in 10-15% of PD and increase disease severity and age of onset. Hypomorphic GBA1 mutations are common and fully penetrant in GD. We developed a brain-penetrant TRPML1 agonist to address lysosomal dysfunction in PD and GD.

CSM-101 was identified following high throughput screening and medicinal chemistry-based optimization. Cellular pharmacological profiling of CSM-101 was performed using assays including whole-cell electrophysiology and high-content imaging. The CBE mouse model (100 mg CBE/kg/qd/ip) was used to evaluate the effects of CSM-101 on survival, brain glucosylsphingosine (GlcSph) and glucosylceramide (GlcCer) as well as plasma neurofilament L (NfL). Separately, rats with unilateral overexpression of a-synuclein (hA53T) in substantia nigra were treated with CSM-101 prior to quantitation of a-synuclein protein and tyrosine hydroxylase-positive neurons.

CSM-101 is a selective, potent and well-tolerated small molecule that fully activates TRPML1 in ePhys and FLIPR assays. Premature lethality in the CBE mouse model is rescued with CSM-101 in a dose-dependent manner. Importantly, key disease biomarkers GlcSph, GlcCer and NfL are also significantly reduced in mice treated with CSM-101. Finally, CSM-101 reduced the levels of a-synuclein by 30% and preserved tyrosine hydroxylase-positive neurons.

CSM-101 is a brain-penetrant TRPML1 agonist that demonstrates significant efficacy in preclinical models of GD and PD. Given the overall profile of CSM-101, this drug candidate is being advanced to evaluate the concept of targeting lysosomal homeostasis in neuronopathic forms of GD and GBA-PD.