Goal

To discover and develop a curative, “single-shot” treatment intervention for HIV and SCD  that is safe, effective, affordable, accessible, and acceptable for those in resource-limited parts of the world.

Background and Current Landscape

Existing management of HIV disease requires lifelong, daily, oral antiretroviral therapy (ART) and is associated with both stigma and access barriers, especially for those people living with HIV (PLWH) in low- and middle-income countries (LMICs). Chronic management of SCD is even less satisfactory and accessible; the two curative ex vivo gene therapies that have been approved in the U.S., U.K., and E.U. remain inaccessible and cost-prohibitive for the vast majority of those in need.

Long-term ART-free virologic control has been observed following transplantation of bone marrow progenitor cells (including hematopoietic stem cells, or HSCs) lacking the HIV co-receptor, CCR5 into PLWH.  Likewise, the approved ex vivo therapies for SCD have demonstrated that upregulation of fetal hemoglobin or insertion of a functional copy of the beta-globin gene into HSCs results in the production of normal red blood cells, preventing the painful crises found in SCD. Gene therapy strategies for both SCD and HIV can involve targeting and editing of HSCs, which would provide the necessary life-long edits to the red blood cell lineage and to the T and myeloid cell lineages for SCD and HIV, respectively. In the case of HIV, additional target cells (including B cells, myocytes, and hepatocytes) might also be targeted and edited for clinical benefit.

For HIV, it is also important to develop gene therapies that prevent re-infection upon subsequent exposure to HIV; hence, approaches towards sustained expression of antagonists of the HIV envelope protein are being pursued.

A key technical challenge is the development of a viral or non-viral delivery strategy for the in vivo targeting of long-lived cells such as HSCs in a safe and efficacious manner, as well as with a cost of goods which is affordable in LMICs.

Investments in this subdomain aim to enable the discovery, design, and development of target interventions by answering the question: can long-lived cells such as HSCs be targeted by viral or non-viral vectors in vivo (e.g., in humanized mouse models and nonhuman primates) and then edited to assume new functional traits that are clinically beneficial (e.g., upregulation of hemoglobin F in the case of SCD)? Proof-of-concept experiments in SCD are anticipated to carry over to modification of HSCs for purposes of HIV cure (e.g., introduction of genes encoding broadly neutralizing antibodies into HSCs while also providing valuable information about the targeting and editing of other long-lived cells of interest, such as B cells, myocytes, and hepatocytes).

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