ARCHE Gene Therapy Grants
Hildegard Büning, Ph.D. – principal investigator
Hannover Medical School, Hannover, Germany
Vector-mediated in vivo targeting of HIV reservoir cells or provirus elimination: To maximize safety of gene therapy, methods to specifically target reservoir cells are required. The HIV reservoir consists mainly of CD4+ T cells, with certain subsets more commonly harboring latent HIV. Dr. Büning plans to design an adeno-associated viral vector that specifically targets one of these main subsets, the central memory T cells. The vector will be designed to carry a gene editing tool called Brec1, previously shown to suppress HIV. One reported advantage of Brec1 over other gene editing tools is the apparent lack of off-target effects.
Keith Jerome, M.D., Ph.D. – principal investigator
University of Washington, Seattle, WA
Subcutaneous administration of DARPin-modified adeno-associated virus vectors for selective targeting of CD4+ T cells: Curing a diffuse disease such as HIV, as opposed to a localized tissue-specific disease, requires a way to target the gene therapy to the target cells of interest, which in HIV are dispersed throughout the body. Dr. Jerome plans to use adeno-associated viral virus vectors engineered to utilize small, antibody-like proteins to target the vectors and their gene-editing cargo directly to CD4+ T cells, which comprise the majority of the HIV reservoir. He will also experiment with ways of infusing the vectors such that they preferentially reach the lymph nodes, where most reservoir cells are found.
Hans-Peter Kiem, M.D., F.A.C.P. – principal investigator
Fred Hutchinson Cancer Research Center, Seattle, WA
Engineering blood cells to produce broadly neutralizing anti-HIV antibodies: Antibodies have been the focus of increasing optimism in the HIV cure research field due to their ability to not only neutralize virus particles, but also to target and help kill infected cells. Dr. Kiem plans to genetically modify immune system progenitor cells to serve as a constant source of antibodies. By engineering cells that will differentiate into a variety of types of immune cells, Dr. Kiem hopes that the progeny cells will migrate to various parts of the body, including lymph nodes and brain known to be important reservoirs of HIV.
Scott Kitchen, Ph.D. – principal investigator
University of California, Los Angeles, Los Angeles, CA
Optimized efficacy and persistence of engineered HIV-specific cellular immunity: Chimeric antigen receptor (CAR) cells have shown remarkable promise in their ability to clear some cancers in patients, and additionally have shown potential in HIV cure. Dr. Kitchen plans to improve the ability of CAR cells to kill HIV-infected cells by increasing their ability to detect the appropriate target cells and prolonging their survival. He also plans to engineer improvements to minimize the loss of CAR cells to attack by the immune system, and to design a mechanism to “switch off” CAR cells should they become unsafe or are no longer needed.
Yasuhiro Takeuchi, Ph.D. – principal investigator
University College London, London, United Kingdom
LentiStim: Mass production of lentiviral vectors for in vivo gene delivery: Curing HIV by gene therapy may require long-term persistence of the gene editing tools delivered by lentiviral vectors, which are closely related to HIV. Because the reservoir that harbors persistent HIV consists almost entirely of resting cells, such vectors cannot gain entry into the cells to deliver their cargo. Dr. Takeuchi plans to modify lentiviral vectors with a cocktail of stimulatory molecules that induce an optimal level of activation in the target cell, thus allowing entry of the vector. The effectiveness of lentiviral vectors is also plagued by immune responses raised against the vector, so the team will produce vectors that are resistant to destruction by the immune system.
Drew Weissman, M.D., Ph.D. – principal investigator
University of Pennsylvania, Philadelphia, PA
Targeting of nucleic acid therapeutics to cure HIV: Gene therapy approaches to cure HIV include efforts to cut the virus out of the human DNA, or to imbue the human host cells with characteristics that protect them from infection. Dr. Weissman plans to employ nucleic acid therapeutics as the tools to edit DNA to achieve either or both of these goals. One advantage of nucleic acid therapeutics is the ability to administer them repeatedly without raising an immune response that would destroy them. He plans to optimize their delivery to the appropriate cells by packaging them inside lipid nanoparticles that can be engineered with surface particles that guide them to specific targets.
Richard Wyatt, Ph.D. – principal investigator
The Scripps Research Institute, La Jolla, CA
Vector-mediated in vivo targeting of HIV reservoir cells or provirus elimination: Chimeric antigen receptor (CAR) cells have shown remarkable promise in their ability to clear some cancers in patients, and additionally have shown potential in HIV cure. One advantage is their ability to overcome a cancer or virus-infected cell’s ability to hide from the immune system. Dr. Wyatt plans to generate CAR T cells with the ability to kill HIV infected cells just as they begin to produce virus. Additionally, the CAR T cells will be engineered to produce antibodies that can neutralize any virus that is produced.