New drug will target mTOR pathway to help clear toxic clumps from brain
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Montara Therapeutics received a $1 million grant from The Michael J. Fox Foundation for Parkinson’s Research (MJFF) to develop a Parkinson’s disease treatment designed to work primarily in the brain and minimize effects on the rest of the body.
The new drug will target the mTOR biological pathway. Previous drugs that block mTOR have shown promise, but unwanted side effects outside the brain have limited their use.
“Our team has spent years working toward a therapy that doesn’t just treat the symptoms of Parkinson’s but addresses the underlying biology causing neurons to die,” Nicholas T. Hertz, PhD, Montara’s founder and CEO, said in a company press release. “The mTOR pathway is one of the most powerful levers we have for clearing toxic proteins from the brain, and our platform may finally make it safe enough to use.”
The grant is part of the MJFF’s Parkinson’s Disease Therapeutics Pipeline Program, which funds preclinical and clinical studies to accelerate the development of new therapies for the disease.
Parkinson’s is caused by the progressive loss of nerve cells that produce dopamine, a signaling molecule involved in motor control. A hallmark of the disease is the formation of toxic clumps of misfolded alpha-synuclein in nerve cells, believed to contribute to nerve cell dysfunction and death.
Dysfunctional autophagy, a cellular cleaning system that degrades or recycles damaged components, including alpha-synuclein clumps, is thought to contribute to alpha-synuclein clumping. The protein mTOR regulates this process: When mTOR is active, autophagy is suppressed; when mTOR is inhibited, the cell’s protein-clearing machinery is active.
According to the company, compounds that inhibit mTOR have shown encouraging results in lab models of Parkinson’s. However, because the protein plays an essential role throughout the body, systemic mTOR inhibition may cause serious side effects, limiting its use for neurological conditions.
“While the underlying biology is compelling, challenges related to systemic toxicity have limited progress,” said Jessica Tome Garcia, PhD, lead scientific program manager, translational research at MJFF. “This work aims to explore approaches that may help address those barriers and advance our understanding of how targeting mTOR-driven autophagy could impact disease biology.”
The company will use its BrainOnly platform to develop an mTOR inhibitor that targets the brain. The platform leverages a two-drug combination therapy: a brain-penetrant, target-specific drug to treat the disease, and a second drug that stays outside the brain and blocks the first drug from affecting other organs.
Montara will evaluate several clinically used mTOR inhibitors in combination with its proprietary peripheral blocker, MT1110, to identify novel two-drug combinations that activate autophagy in the brain. The company will assess which combinations exhibit favorable safety profiles and more effectively reduce alpha-synuclein clumping and treat the disease, using cell-based systems and animal models of Parkinson’s.
The project aims to identify a potential therapeutic strategy that safely improves autophagy to clear toxic protein accumulation, slowing or stopping disease progression.
“Our own genome-wide screens in human neurons identified mTOR signaling as one of the key pathways controlling the accumulation of toxic protein aggregates — and a target with real therapeutic potential,” said Martin Kampmann, PhD, professor at the University of California, San Francisco and Montara’s scientific co-founder. “Montara’s BrainOnly platform is the most compelling approach I’ve seen for solving that problem, and this program gives us a direct path to test whether brain-selective mTOR inhibition can reduce pathological protein buildup in Parkinson’s disease.”
The company previously received a $3.3 million MJFF research grant to develop a brain-selective LRRK2 inhibitor drug candidate that avoids the problems associated with blocking LRRK2 in peripheral organs. Mutations in the LRRK2 gene are one of the most common genetic causes of Parkinson’s, typically causing the overactivation of the LRRK2 enzyme that contributes to neurodegeneration.
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