Objective: (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.

Background: Lysosomal homeostasis is critical for efficient catabolism 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 loss of function mutations in GBA1, which encodes the lysosomal enzyme GCase, are reported in 15-20% of PD. These GBA-PD patients have increased age of onset and disease severity. Hypomorphic GBA1 mutations are common and fully penetrant in GD. We developed CSM-101 as a novel small molecule agonist for the lysosomal ion channel TRPML1 and a drug candidate for GD and PD.

Method: 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. CSM-101 was used to treat primary mouse cortical neurons incubated with conduritol beta epoxide (CBE), a GCase inhibitor. The levels of glucosylsphingosine were determined using LC-MS. Mice were treated with CBE (50 and 100 mg/kg delivered i.p.) and effects of CSM-101 on mouse survival were determined. Rats with unilateral overexpression of a-synuclein (hA53T) in substantia nigra were treated with CSM-101 for 6 weeks prior to quantitation of a-synuclein protein and tyrosine hydroxylase-positive (TH⁺) neurons.

Results: CSM-101 is a selective and potent TRPML1 agonist that is well tolerated in rodents. In the primary neuron CBE model, CSM-101 significantly reduced levels of glucosylsphingosine. Importantly, the premature lethality seen in CBE-treated mice was significantly delayed following daily dosing with CSM-101. Finally, CSM-101 reduced levels of a-synuclein by 30% and preserved TH⁺ neurons.

Conclusion: CSM-101 is a brain-penetrant TRPML1 agonists 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.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/csm-101-is-a-small-molecule-agonist-of-trpml1-for-parkinsons-related-disorders/