A New Approach to Challenging Targets
First-in-class small molecules for challenging targets in diseases with high unmet need
Targeting TDP-43 to treat amyotrophic lateral sclerosis (ALS)
TDP-43: A shapeshifting cellular regulator and major contributor to neurodegeneration
TDP-43 is a vital protein involved in a wide range of cellular activities, most notably including regulation of mRNA splicing. It is involved in many neurodegenerative diseases and is the most critical regulator of the cascade of inflammatory reactions that leads to ALS. This cascade contributes to ongoing cellular stress and eventually the death of motor neurons.
In ALS, loss of motor neurons gradually limits people’s muscle control, eventually leading to the inability to swallow and breathe. There are approximately 30,000 people living with ALS in the United States, and the average lifespan after diagnosis is two to five years. There are no approved therapies that address the cause of the disease or significantly slow its progression.
ACE-2223 is a small molecule designed to specifically target gain-of-function related, misfolded forms of TDP-43 that lead to disease pathology.
In ALS, TDP-43 accumulates as large inclusions or aggregates in the cytoplasm via a toxic hexameric intermediate. These misfolded hexameric and aggregated forms lead to a loss of TDP-43 function normally carried out by monomeric and dimeric forms in the nucleus. The lack of healthy TDP-43 leads to a breakdown of mRNA function, resulting in a range of incorrect or missing proteins throughout the cell.
The complexity of misfolded TDP-43 has historically made TDP-43’s structure hard to analyze. It has also rendered difficult the design of drugs that directly target it – until our work at Acelot.
Mass removal of TDP-43 from neurons leads to cellular death, so an ideal drug mechanism disrupts the TDP-43 diseased form specifically, pushing the equilibrium of TDP-43 aggregated forms towards prevalence of the healthy forms in their functional location in the nucleus. This functional TDP-43 can then appropriately regulate mRNA splicing and correct translation of a wide range of proteins.
ACE-2223: Our solution to restore TDP-43’s healthy form and function
Data supporting ACE-2223
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Highly blood-brain-barrier (BBB) permeable
Reduces pathological TDP-43
Rescues neuroinflammation
Reduces neurofilament-light chain
Improves survival and motor function
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Inhibits TDP-43 aggregation
Dissociates preformed TDP-43 aggregates
Rescues mRNA mis-splicing
Rescues functional TDP-43
Increases neuronal survival
Improves synaptic defects
Our work begins with de novo drug design to target proteins whose complex form and behavior make them challenging targets. We integrate novel AI tools, computational chemistry and assays to design and optimize small molecule candidates against these targets to create the promise of first-in-class and best-in-class drugs for devastating diseases.
The targets Acelot is pursuing have demonstrated potential applicability in a range of neurodegenerative diseases, including TPD-43 positive fronto-temporal dementia, Alzheimer's disease (AD), inclusion body myositis, multiple system atrophy, and dementia with Lewy bodies.
Our team is focused on rigorous science and efficient development to accelerate the delivery of first-ever treatment options. We collaborate closely with leading scientists and experts in disease biology, and our backgrounds include the deep technical, discovery and entrepreneurial experience essential for pharmaceutical development.
Management Team
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Katie Planey, PhD, MBA
Chief Executive Officer
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Lewis Whitehead, PhD
Vice President of Research, Computational Discovery
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Vidhu Mathur, PhD
Senior Director, R&D
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Valarie Truax, PhD, MBA
Head of Business Development
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Marcie Glicksman, PhD
Acting Chief Scientific Officer
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Shruti Arya, PhD
Senior Scientist I
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Andrew Carr, PhD
Senior Scientist
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Marcela Kokes, PhD
Senior Scientist I
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Devi Supriya Korumilli, MS
Research Associate
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Cody Aldaz, PhD
Data Scientist
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Kevin Burk, MS, MSci
Data Scientist
Advisors
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Ambuj Singh
Founder & Board Member, Acelot; UCSB Professor, Department of Computer Science, Biomolecular Science and Engineering
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David Bleakman
President, Drug Discovery Psychogenics; Former CSO, Eli Lilly Neuroscience; Former CSO, Redpin Therapeutics
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Andrew Perlman
Co-founder & Managing Director, X37; Former EVP, Tularik; Former CEO, Innate Immune; Former Director of Clinical Development, Genentech
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Mike Kavanaugh
CSO, Cytomx; Former CSO, Five Prime Therapeutics; Former VP, Novartis Vaccines & Diagnostics