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OUR SCIENCE

Cellular phenotyping-enabled drug discovery

Pursuing genetically validated targets with a focus on autophagy pathways by uniting machine learning-enabled image-based cell profiling, chemistry and computational sciences to discover novel small molecules to treat severe neurodegenerative diseases.

How we address biological questions at scale

Phenotype-focused biology
Phenotype-focused biology

We use high content imaging of human-derived cells to extract cellular features and generate hundreds of phenotypic profiles. By deploying machine learning-enabled modeling, we can rapidly pinpoint the clusters and classifiers that separate diseased versus healthy state signatures to better understand how biological pathways regulate cellular behaviors and how dysregulation leads to disease.

Computational and medicinal chemistry
Computational and medicinal chemistry

Our drug discovery strategy combines inventive structure-based hypotheses with computational methods to devise novel approaches to modulating protein function.

We apply our medicinal chemistry expertise and mathematical/physics-based modeling to high value biological targets with unexploited modalities such as allosteric activation and molecular glues to identify novel small molecule drugs.

Mechanistic biomarkers
Mechanistic biomarkers

We identify target- and disease-specific biomarkers for pathway engagement and patient stratification to increase the likelihood of success in our clinical trials.

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Boosting autophagy to restore neuronal function

A vital natural pathway

Autophagy is a natural and essential biological process that plays a crucial role in maintaining cellular homeostasis, eliminating damaged or dysfunctional cellular components, and recycling nutrients. Using autophagy a cell removes waste to renew itself and stay healthy. Defects in autophagy have been implicated in the pathogenesis of various diseases, including neurodegenerative disorders.

A critical role in neurodegeneration

Dysregulation of autophagy can lead to detrimental consequences in the brain, such as aggregation of toxic proteins, impaired energy supply, cellular stress, and inflammation. Human genetic studies have linked mutations in the autophagy-lysosomal pathway to neurodegenerative diseases such as Parkinson’s disease, ALS, and Alzheimer’s, and other non-neurological disorders.

Restoring neuronal function to alter the trajectory of neurodegenerative disease

Nine Square is developing compounds that activate autophagy pathways to enhance clearance of aggregated proteins and lipids, remove damaged mitochondria, and restore cellular homeostasis to mitigate neurodegeneration.

  Autophagy is the body’s own cellular degrading machinery that clears toxic proteins and damaged organelles such as mitochondria through a mechanism mediated by lysosomes — small vesicles that contain protein-degrading enzymes — to restore normal function.

About Us

OUR SCIENCE

LEGAL

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James B. Summers, Ph.D.
Pharmaceutical Research and Strategy Advisor
During more than 30 years with Abbott and AbbVie, Dr. Summers held various senior R&D leadership positions, including vice president of neuroscience research, where he led efforts located in Ludwigshafen, Germany, Lake County, IL and Cambridge, MA, focused on the discovery of new drugs for the treatment of Alzheimer’s and Parkinson’s diseases, pain and psychiatric disorders. Under his leadership, the teams advanced more than 20 compounds into clinical development. Currently Dr. Summers serves as a board member and advisor to several biotechnology companies. He is also a venture partner with the Dementia Discovery Fund. Dr. Summers earned a Bachelor of Science in Chemistry, summa cum laude, from Denison University and a Doctorate in Organic Chemistry from Harvard University.
Roberto Zoncu, Ph.D.
SAB Member

Roberto is a professor of Molecular Therapeutics in the Department of Molecular and Cell Biology at the University of California, Berkeley. Prior to UC Berkeley, Roberto was a postdoctoral fellow at MIT’s Whitehead Institute, where he worked in Dr. David Sabatini’s laboratory. Roberto combined biochemical and microscopy-based assays to understand how lysosomes govern the signaling activity of the master growth regulator, mTORC1 kinase, and how these organelles generally function as metabolic signaling centers. For his doctoral studies, Roberto joined Dr. Pietro De Camilli’s laboratory. He used advanced microscopy and chemical genetic techniques to interrogate how a class of phospholipids known as phosphoinositides control endocytic vesicle traffic and maturation.

Roberto holds a Ph.D. in Cell Biology at Yale University. He studied molecular biology at the University of Pisa in Italy.

Aimee Kao, M.D., Ph.D.
SAB Member

Aimee is the John Douglas French Foundation Endowed professor at the University of California San Francisco School of Medicine and associate professor of Neurology at the University’s Weill Institute for Neurosciences. Aimee’s laboratory studies the basic mechanisms underlying neurodegenerative disorders. She is an expert in the diagnosis and treatment of age-related cognitive conditions such as Alzheimer’s disease, Lewy body disease and frontotemporal lobar degeneration.An award-winning scientist, Aimee She maintains an active clinic at UCSF’s Memory and Aging Center. At UCSF, she teaches medical students and serves as a research mentor to UCSF undergraduates for both theSummer Research Training Program (SRTP)and San Francisco Building Infrastructure Leading to Diversity (SF BUILD) program. Aimee also co-chairs the Neuroscience graduate program’s Diversity, Equity and Inclusion Committee.

Aimee completed her internship at the Beth Israel Deaconess Medical Center, residency in neurology at University of California, San Francisco, where she was chief resident, and received fellowship training in behavioral neurology and molecular genetics. She holds an MD and Ph.D. from the University of Iowa Carver College of Medicine and BS fromBrown University. She joined the UCSF faculty in 2007.

Robert Edwards, M.D.
SAB Member

Robert is the Cahill professor of Neurology and Physiology at the Weill Institute for Neurosciences at the University of California San Francisco School of Medicine. His work focuses on the molecular and cellular basis of neurotransmitter release and its role in Parkinson’s disease. In his research, he and his colleagues have identified several proteins implicated in Parkinson’s disease. Robert joined University of California, San Francisco from the faculty at University of California, Los Angeles. Among Robert’s many awards is the Established Investigator Award of the National Alliance for Research on Schizophrenia and Affective Disorders. He serves on editorial boards of several journals and the scientific advisory board of the Parkinson’s Foundation. He is a member of the National Academy of Medicine and the National Academy of Sciences.

He studied as a postdoctoral fellow with William J. Rutter after completing residency in clinical neurology at UCSF. Robert completed his M.D. at Johns Hopkins University School of Medicine and BA at Yale College. 

Sami Barmada, M.D., Ph.D.
SAB Member

Sami is the Angela Dobson Welch and Lyndon Welch research professor and associate professor of Neurology at University of Michigan and director of the University’s Michigan Brain Bank. Sami’s research focuses on combining basic biology with translational research and technology development to investigate unanswered questions in neurodegenerative diseases. His lab uses innovative technologies and methods involving fluorescence microscopy, computer science and engineering, bioinformatics, genome engineering and molecular biology to investigate critical abnormalities in RNA and protein metabolism in ALS and FTD.

Sami received his Ph.D. in the Medical Scientist Training Program at Washington University in St. Louis, where he investigated prion diseases. He went on to train with some of the premier clinicians and scientists in neurodegenerative diseases, such as Bruce Miller and Cathy Lomen-Hoerth while at University of California, San Francisco for his neurology residency. Throughout residency and postdoctoral fellowship, Sami worked with Steve Finkbeiner at the Gladstone Institutes, where he established one of the first human neuronal models of familial ALS and FTD.

Sami serves on the executive advisory board of the Robert Packard Center for ALS Research and scientific advisory boards of the Live Like Lou Foundation and Synapticure, Inc. He takes an active role in their efforts to raise awareness of ALS.

John Hood, Ph.D.
Endeavor Biomedicines

John is a 20-year veteran of the life sciences community in California and has founded and led several successful biotechnology companies. He is currently founder, chief executive officer and executive chairman of Endeavor Biomedicines, which was funded in 2021 to develop novel therapeutics for oncology and idiopathic pulmonary fibrosis. John has founded and led several other successful biotechnology companies including the now Bristol-Myers-Squibb-owned Impact Biomedicines, of which he was Founder and CEO.

He began his career in 2001 as director of research at TargeGen, where he co-discovered fedratinib, a treatment option approved worldwide for myelofibrosis, and led a team identifying small molecule therapeutics for cancer and eye disease. John is an inventor on more than 100 patents and author of more than 50 scientific articles.

He received a Ph.D. in Medical Physiology and a B.S. in Biochemistry from Texas A&M University.

Michael Ehlers, M.D., Ph.D. Apple Tree Partners (ATP)
Mike is general partner and chief scientific officer at Apple Tree Partners (ATP), where he applies expertise gained through a successful career leading research and development at major biopharmaceutical companies. He co-founded ATP’s portfolio companies Intergalactic Therapeutics (Cambridge, MA), Aulos Bioscience (Cambridge, MA), Ascidian Therapeutics (Boston, MA), and Replicate Bioscience (San Diego, CA). Prior to ATP, Mike was executive vice president of Research and Development at Biogen, where he led discovery sciences, translational medicine, clinical development, and regulatory sciences with a focus on neurological, immunological, and rare diseases. He expanded and diversified Biogen’s clinical portfolio, transformed its R&D productivity, advanced more than 20 novel clinical candidates, and oversaw global filings and approvals of Spinraza™ (nusinersen), the first drug approved for spinal muscular atrophy. Prior to Biogen, Mike was senior vice president at Biotherapeutics and chief scientific officer of Neuroscience at Pfizer. While there, he created and advanced the neuroscience and rare disease portfolios,directed global development activities in biologics design, synthesis, and manufacturing, steered academic collaborations focused on immunology and oncology,and brought 22 compounds into the clinic.  Before entering industry, Mike was a professor and investigator at the Howard Hughes Medical Institute at Duke University Medical Center. Hee pioneered studies on neuronal organelles and the trafficking of neurotransmitter receptors. He has received numerous awards, authored more than 100 scientific papers, and served on multiple editorial and advisory boards for the National Institutes of Health, private foundations and many other organizations across industry, academia and government.h Mike holds an M.D. and Ph.D. from Johns Hopkins University School of Medicine and  a B.S. in Chemistry from California Institute of Technology.
Lani Wu, Ph.D., and Steve Altschuler, Ph.D. (Observers)
Nine Square Therapeutics
University of California, San Francisco

Lani and Steve are co-founders of Nine Square Therapeutics and professors in the Department of Pharmaceutical Chemistry at the University of California, San Francisco . They together tackle systems-level questions in biology, disease and pharmacology in their laboratories at UCSF, where they developed a research program that combines experimental biology, data sciences and modeling to attack fundamental problems in cell biology and drug discovery. They entered systems biology and pharmacology through Rosetta Inpharmatics, a biotech startup. Their research careers started in mathematics at the interface of analysis and geometry, in which they found diverse applications, including the Poincaré Conjecture, robotics and computer graphics. They transitioned to engineering at Microsoft, co-leading an invention team that developed machine learning approaches to improve human-computer interactions in areas including computer vision, social networking and noisy speech recognition.  

Lani and Steve are pioneering members of the Bauer Fellows Program at Harvard University and the Green Center for Systems Biology at University of Texas Southwestern Medical Center, and visiting faculty at Mathematical Scientists Research Institutes in Berkeley and Google Brain in Mountain View.

Matthew P. Jacobson, Ph.D.
Nine Square Therapeutics
Apple Tree Partners (ATP)
University of California, San Francisco

Matthew P. Jacobson is a co-founder of Nine Square Therapeutics, a venture partner at Apple Tree Partners (ATP), and a biotech entrepreneur who has co-founded several other successful companies including Global Blood Therapeutics, Circle Pharma, and Relay Therapeutics. A Professor Emeritus in the Department of Pharmaceutical Chemistry at University of California San Francisco, he is a leading authority in computer-aided drug design and computational structural biology and biophysics. His research interests include docking against homology models and flexible protein binding sites, membrane permeability, antibody modeling, mechanisms of protein regulation by post-translational modifications, allostery, and pH. He is author of more than 200 research publications, the recipient of an NSF CAREER award and an Alfred P. Sloan Fellowship, and holder of several patents. Software written by Matt and his collaborators is widely used in the pharmaceutical industry.

Matt earned a Ph.D. in physical chemistry from the Massachusetts Institute of Technology in 1999 and did his postdoctoral work at Oxford University and Columbia University.

Spiros Liras, Ph.D.
Nine Square Therapeutics
Apple Tree Partners (ATP)

Spiros is co-founder of Nine Square Therapeutics and venture partner at Apple Tree Partners (ATP). He brings to ATP his decades-long career leading scientific innovation and discovery at some of the world’s foremost pharmaceutical companies. At ATP, Spiros  co-founded its portfolio companies Nereid Therapeutics (Cambridge, MA) , Initial Therapeutics (San Francisco, CA), Evercrisp Biosciences (Berkeley, CA), Deep Apple Therapeutics (San Francisco, CA), and Apertor Pharmaceuticals (Alameda, CA).

Prior to ATP, Spiros established and led the External Portfolio Innovation unit within Research and Development at Biogen. Prior to Biogen, he was vice president of Medicinal Chemistry at Pfizer, where he led teams to deliver clinical pipelines in disease areas including cardiovascular, metabolic and neuroscience. Under his leadership, his divisions explored cutting edge drug discovery concepts including selective protein translation inhibition, design of macrocycles for drug discovery in tough target space, allosterism, and tissue targeting design strategies for the delivery of small molecule, oligonucleotide therapeutics and other modalities.

Spiros earned a Ph.D. in Organic Chemistry from Iowa State University and completed postdoctoral studies at the University of Texas at Austin. Spiros is an adjunct professor in the Department of Pharmaceutical Chemistry at the University of California, San Francisco.

Parkin

Parkin is an intracellular protein that regulates mitochondrial quality control by selectively promoting the degradation of dysfunctional mitochondria, and Parkin mutations are implicated in early-onset Parkinson’s disease (PD). Nine has small molecule candidates that promote Parkin activity in lead optimization for PD, and plans to nominate a clinical candidate by [date].

TRPML1

TRPML1 is a lysosomal membrane protein that promotes autophagy by releasing calcium ions from the lysosome, and defects in the TRPML1 pathway have been linked to autophagic disorders and amyotrophic lateral sclerosis (ALS). Nine Square is evaluating small molecule candidates that activate TRPML1 to treat ALS, and plans to nominate a clinical candidate by the end of 2023.
Seth Harrison, M.D.
Apple Tree Partners (ATP)

Seth Harrison is a founder and managing partner of Apple Tree Partners (ATP), where he oversees $2.65 billion in committed venture capital. Since starting the firm in 1999, Seth has launched or invested in more than 30 companies focused on delivering cutting-edge therapies for unmet medical needs, with 19 now public or acquired. Prior to ATP Seth was a venture partner at Sevin Rosen Funds and a general partner at Oak Investment Partners.

Seth received an M.D. and MBA from Columbia University, completing a surgery internship at the Presbyterian Hospital in the City of New York. He earned an A.B. from Princeton University. He served on the board of the International Partnership for Microbicides from 2002-2010.

Robert holds an M.D. and Ph.D. from Ludwig-Maximilians Universität München in Germany and is a board-certified neurologist.

Robert Paul, M.D., Ph.D.
Chief Executive Officer

Robert has more than 20 years of experience in business and clinical development for neurodegenerative diseases. He joined Nine Square Therapeutics as CEO in January 2022 after serving as the chief medical officer of Alector, a leading immuno-neurology and immuno-oncology company. Robert joined Alector from Genentech, where he held leadership roles in the company’s Medical and Neuroscience Clinical Development organizations from 2009 to 2016. Prior to joining Genentech, Robert was a neurologist at the University of Munich and a consultant at Boston Consulting Group.

Robert holds an M.D. and Ph.D. from Ludwig-Maximilians Universität München in Germany and is a board-certified neurologist.