UPMC: Pittsburgh Project to Pave Way for Technology to Revolutionize Treatment of Fatal Brain Diseases


A collaborative group of neuroscientists from the University of Pittsburgh School of Medicine and Carnegie Mellon University received a $6.8 million grant from the National Institutes of Health (NIH) Brain Research Through Advancing Innovative Neurotechologies® (BRAIN) Initiative to create an ultra-high resolution molecular atlas of the brain and develop brain cell type-specific strategies for effective and precise gene delivery.

The research will leverage genetic information resolved with single-cell precision to establish a comprehensive database of cell types and neural circuits comprising the brain’s cognitive and reward systems. In combination with ultra-high-resolution magnetic resonance imaging (MRI), the researchers intend to build brain atlases of marmosets and macaque monkeys and make them available to other neuroscientists across the world, free of charge.

StackedGrayNamespress“This award enables cross-disciplinary collaboration between experts in neural imaging, gene therapy, machine learning, and molecular biology to advance our understanding of single-cell level organization of the brain’s essential systems,” said project principal investigator William Stauffer, Ph.D., assistant professor of neurobiology at Pitt. “We hope this unmatched degree of precision will eventually pave the way for the development of effective and precise gene editing technologies that might revolutionize treatment of previously fatal diseases, such as Alzheimer’s or Parkinson’s.”

The recently launched BioForge Initiative, backed by Pitt Senior Vice Chancellor for the Health Sciences, Anantha Shekhar, M.D., Ph.D., will be used to advance the wide-scale production and commercialization of the gene delivery vectors identified with the grant support.

“We are excited that the services of a state-of-the-art biomanufacturing facility will soon be available in Pittsburgh to help make the lofty goal of delivering new and improved medical treatments for brain disorders a reality,” said Shekhar. “It feels very special to participate in a program that will not only bring life-saving treatments to our patients but also facilitate the dissemination of Pitt-developed technologies to research labs around the world and take a big step toward creating products with economic impact on the region.”

The BRAIN Initiative® was announced in 2013 to deepen understanding of the inner workings of the human mind and over the years has grown to prioritize the expansion of molecular cell-type profiling and data analysis, enabling genetic and non-genetic access to cell types across multiple species. The multi-year NIH grant was awarded as part of the Armamentarium for Precision Brain Cell Access, a large-scale NIH BRAIN Initiative project.

“Delivery technologies for specific brain cell types are revolutionizing experimental neuroscience by allowing researchers to probe the cells and circuits underlying complex behaviors,” said John Ngai, Ph.D., Director of the NIH BRAIN Initiative. “An expanded toolkit of precision brain cell access tools supported by the first phase of the Armamentarium project could ultimately inform cell- and circuit-specific therapies for human patients, for example, those with epilepsy, neurodevelopmental diseases, or mood disorders.”

Projects like the one led by Stauffer, who is interested in defining how different cell types contribute to behavior, as well as investigating cell type-specific disease processes, are essential to the Initiative’s mission. Stauffer and his close collaborators, Leah Byrne, Ph.D., assistant professor of ophthalmology at Pitt, and Andreas Pfenning, Ph.D., assistant professor of computational biology at CMU, were awarded a BRAIN Initiative grant in 2018 to begin defining the molecular profiles of different neuron types.

“Even a small piece of brain tissue contains dozens of different subtypes of neurons, each performing different functions during different behaviors,” said Pfenning, who is a part of CMU’s Neuroscience Institute. “The ability to target these populations using viruses could accelerate basic research and also pave the way for targeted therapeutics.”

Pfenning’s group will use custom-made machine learning models and evolutionary theory to identify sequences that are most likely to label subpopulations of neurons. His laboratory will also test the ability of those sequences to target specific cell types in the mouse brain.

Further building on the molecular profiling data, scientists at Pitt’s Brain Institute intend to identify cell type-specific drivers of gene expression in the forebrain and the frontal lobe and develop ready-to-use, specific and efficient gene delivery vectors, including adeno-associated viruses (AAVs). To develop novel AAVs, they will use scAAVengr, the single cell AAV engineering pipeline developed by Byrne. The team will combine scAAVengr-optimized AAV viral shells with newly identified cell type-specific enhancers, and the combination of these elements will generate viral vectors capable of delivering highly efficient and cell type-specific gene therapies. Afonso Silva, Ph.D., professor of neurobiology who holds an endowed chair in translational neuroimaging at Pitt and also a member of the Brain Institute, joins Stauffer, Byrne and Pfenning on the project team. The Silva lab will create an ultra-high resolution MRI atlas of the rhesus monkey brain. That MRI-based atlas will provide the framework for detailing how viral vector expression is controlled in a brain-wide fashion.