A new approach to Parkinson's treatment could finally unlock the therapeutic potential of a powerful protein-clearing pathway without the dangerous side effects that have limited its use for decades. Montara Therapeutics received a $1 million grant from The Michael J. Fox Foundation for Parkinson's Research (MJFF) to develop a brain-targeted drug that activates the mTOR pathway, a cellular mechanism that helps clear the toxic protein clumps responsible for nerve cell death in Parkinson's disease.

Why Has mTOR Been So Difficult to Target?

Parkinson's disease develops when nerve cells that produce dopamine, a chemical messenger essential for movement control, gradually die. A hallmark of the disease is the accumulation of misfolded alpha-synuclein proteins that clump together inside nerve cells, contributing to their dysfunction and death. The body has a natural cleanup system called autophagy that degrades these toxic clumps, but in Parkinson's patients, this system doesn't work efficiently.

The mTOR protein regulates autophagy: when mTOR is active, the cleanup system shuts down; when mTOR is inhibited, cells can clear away damaged proteins more effectively. Scientists have known for years that blocking mTOR could theoretically help Parkinson's patients, but there's a critical catch. mTOR plays essential roles throughout the entire body, not just the brain. When researchers have tried to inhibit mTOR systemically, patients experience serious side effects in their organs, muscles, and immune systems, making the treatment too dangerous to use.

"While the underlying biology is compelling, challenges related to systemic toxicity have limited progress," explained Jessica Tome Garcia, PhD, lead scientific program manager for 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."

Jessica Tome Garcia, PhD, Lead Scientific Program Manager, Translational Research at MJFF

How Does the BrainOnly Platform Work?

Montara's solution is elegantly simple in concept but complex in execution. The company developed a platform called BrainOnly that uses a two-drug combination strategy. The first drug penetrates the blood-brain barrier and inhibits mTOR specifically in brain tissue. The second drug, called MT1110, stays outside the brain and blocks the first drug from affecting organs and tissues elsewhere in the body. Think of it as a targeted delivery system with a built-in safety switch.

The company will test several existing mTOR inhibitors paired with MT1110 to identify which combinations most effectively activate autophagy in the brain while maintaining safety. Researchers will evaluate these combinations using cell-based systems and animal models of Parkinson's to determine which shows the most promise for reducing alpha-synuclein clumping and slowing 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," stated 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."

Martin Kampmann, PhD, Professor at University of California, San Francisco and Scientific Co-Founder at Montara Therapeutics

Steps to Understanding This Treatment Approach

• The Problem: Parkinson's patients accumulate toxic alpha-synuclein protein clumps in their brain cells, which the body's natural cleanup system (autophagy) cannot efficiently remove, leading to nerve cell death.
• The Target: The mTOR protein controls autophagy activation, but blocking it throughout the body causes serious side effects in organs and tissues outside the brain, making systemic mTOR inhibitors unsafe for patients.
• The Solution: Montara's BrainOnly platform uses two drugs working together: one that crosses into the brain to inhibit mTOR, and another that blocks it from affecting the rest of the body, potentially offering safety without sacrificing efficacy.

This grant represents part of a broader momentum in Parkinson's research. Montara previously received a $3.3 million MJFF grant to develop a brain-selective inhibitor targeting the LRRK2 gene, mutations in which cause one of the most common genetic forms of Parkinson's. The company's track record suggests the organization has successfully applied similar brain-targeting principles to multiple disease pathways.

Why This Matters Now for Parkinson's Patients

California is emerging as the epicenter of Parkinson's research innovation. At UC San Francisco, researchers have developed adaptive deep brain stimulation technology that reads brain signals in real time and adjusts treatment automatically. At UC San Diego, scientists have reprogrammed brain cells to replace the dopamine-producing neurons that Parkinson's destroys, reversing symptoms in early preclinical models. These breakthroughs demonstrate that the field is moving beyond symptom management toward disease-modifying treatments.

The scale of the challenge is substantial. More than 1.2 million people in the United States, including nearly 135,000 Californians, live with Parkinson's and related conditions today. Parkinson's is the world's fastest-growing neurological disease, and in 2024 alone, the disease cost patients, families, and taxpayers across the country $82 billion. This includes direct medical costs as well as indirect expenses like premature retirements, lost savings, and unpaid caregiver burden.

Yet the scientific landscape has shifted dramatically. Nearly two dozen new Parkinson's treatments have been approved in the last decade, and more than 175 are currently in clinical development. Notably, half of those in development aim to slow or entirely stop the disease rather than merely treating its symptoms, something that was not previously possible. In 2023, scientists validated the first test that can detect Parkinson's biology in living humans years before symptoms appear, opening the door to earlier intervention and potentially prevention.

Montara's mTOR-targeting approach represents exactly this kind of disease-modifying strategy. By safely clearing toxic protein accumulation, the treatment could theoretically slow or halt neurodegeneration rather than simply managing tremor, rigidity, and movement slowness. The $1 million MJFF grant will fund preclinical research to identify the safest and most effective drug combination, with the goal of eventually advancing to human clinical trials.