Palo Alto Veterans Institute For Research

Cell Atlas of Human Intestinal Lumphoid Tissues and Changes in Crohn's Disease: Eugene Butcher, M.D. The Helmsley funded project is part of a multi-year research study designed to generate a comprehensive atlas of the gastrointentinal (GI) tract at single cell resolution. Our focus is on the lymphoid tissues and immune cells of the gut wall in healthy and Crohn's disease patients, and in cooperation with our colleagues from Lund University of Sweden, we have produced transcriptomal profiles of over a million cells representing both immune (esp CD4 lymphocytes) and stromal cell populations.continued in Schedule OThese data are being incorporated into public datasets with interactive interfaces to allow scientists throughout the world to mine them for insights into the healthy and diseased intestinal immune system. This year we continued integration efforts towards this end. In addition, we used our generated data with others for key insights into the complexity, tissue imprinting, and lineage-specific precursors within the mononuclear phagocyte compartment of the human intestines. And the project data generated at the VA Palo Alto supported our discovery of a novel lymphocyte trafficking program, the CXCL17-GPR25 axis that directs lymphocytes and controls immune responses and tolerance in non-intestinal mucosa including the airways, nose, eye, stomach, oral cavity, vagina and GU tract and biliary tract (Nature, 2024). The study has yielded over 25 peer reviewed manuscripts, with this seminal Nature study published in the last year. Additionally, presentations at both national and international meetings have been made to share the progress of this study.

Clinical Translation of Allogeneic Regenerative Cell Therapy for White Matter Stroke and Vascular Dementia: Irene Lorenzo Llorente, Ph.D.Stroke is the leading cause of adult disability and the second leading cause of dementia. White matter stroke (WMS) constitutes up to 30% of all stroke subtypes and it is a distinct process from "large artery stroke". continued in Schedule OWMS starts as small infarcts in deep penetrating blood vessels in the brain but progresses, accumulates, and expands from preexisting lesions into adjacent white matter to produce hemiparesis with incomplete recovery, gait abnormalities, cognitive decline, and difficulties in executive functioning that present as vascular dementia. Unlike "large artery stroke", WMS does not damage neuronal cell bodies but damages axonal tracts and glial cells. Therefore, a cell-based therapy that can replace lost glia and induce structural repair in WMS/VaD is of great promise. We have developed a unique allogenic human induced pluripotent stem cell (hiPSC) derived Glial Enriched Progenitor (GEP) cell therapy product for the treatment of WMS and VaD. We have demonstrated that hiPSC-GEPs transplanted into the brain after WMS/VaD promoted motor and cognitive recovery through 3 mechanisms of action: axonal growth, astrocytic modulation, oligodendrocyte differentiation, and remyelination. To date, we have also qualified the entire manufacturing process for the intended therapeutic candidate, hiPSC-GEPs, through safety, identity, purity, activity, and stability qualification assays. To demonstrate the scale-up manufacturing capabilities of the potential therapeutic product, we have developed a new cGMP manufacturing protocol and produced well above the necessary number of cells for phases 1 and 2 of a future clinical application. This preliminary work could pave the way for a faster route to pre-IND, FDA approval, and a future clinical application.

PAVIR is privileged to work with a large community of uniquely talented medical researchers across a broad spectrum of research areas as we fulfill our mission of advancing Veterans and public health through innovative research. The range of research activities is broad and includes special emphasis on major disease categories, all of which are prevalent in the VA's patient population. These include cardiovascular medicine, mental health, chronic inflammatory disease, stem cell/regenerative medicine, pain, sleep disorders, and many others. In addition to disease specific research, PAVIR is engaged in supporting research aimed at enhancing health care. PAVIR's research portfolio includes comparative studies in which research teams are learning which treatments are superior to others, how to augment or improve standard of care, as well as how to enhance the operation of health care. Furthermore, PAVIR is supporting educational activities, especially in areas of advancing clinical care for Veterans and fostering the professional development of our expert staff.