A New Approach to Challenging Targets
Small molecules for challenging targets in diseases with high unmet need
Targeting TDP-43 to treat amyotrophic lateral sclerosis (ALS)
TDP-43 is the most critical regulator of the cascade of reactions that leads to ALS
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 misfolded TDP43 that leads to disease pathology.
In ALS, TDP-43 accumulates as large inclusions or aggregates in the cytoplasm via a toxic hexameric intermediate. These misfolded 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, an ideal drug mechanism disrupts the disease-associated form of TDP-43, thus shifting the equilibrium back to the healthy form of TDP-43. 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
Click above for a snapshot of the biology involved
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.
* Acelot is pursuing targets that have demonstrated potential applicability in a range of neurodegenerative diseases, including TDP-43 positive fronto-temporal dementia, Alzheimer's disease (AD), inclusion body myositis, multiple system atrophy, and dementia with Lewy bodies.
Novel AI tools &
computational chemistry
Functional assays
Small molecule
optimization
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.
Our Cultural Values
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
Vice President, Business Development and Corporate Strategy
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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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Vanessa Seawright, MS
Research Associate
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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, PhD
Founder & Board Member, Acelot; UCSB Professor, Department of Computer Science, Biomolecular Science and Engineering
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David Bleakman, PhD
President, Drug Discovery Psychogenics; Former CSO, Eli Lilly Neuroscience; Former CSO, Redpin Therapeutics
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Andrew Perlman, MD, PhD
Co-founder & Managing Director, X37; Former EVP, Tularik; Former CEO, Innate Immune; Former Director of Clinical Development, Genentech
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Mike Kavanaugh, MD, PhD
CSO, Cytomx; Former CSO, Five Prime Therapeutics; Former VP, Novartis Vaccines & Diagnostics
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Steve Doberstein, PhD
Former Chief Scientist, Nektar Therapeutics; Former Senior R&D, XOMA Royalty; Former Senior R&D, Five Prime Therapeutics; Former Senior R&D, Xencor; Former Senior R&D, Exelixis