# In vivo HSC gene therapy using a multi-modular HDAd vector for HIV cure

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $658,154

## Abstract

Hematopoietic stem cell (HSC) transplantation can provide durable HIV elimination as exemplified in the “Berlin”
patient, the “London” patient, and recently, in a third (“New York”) patient. This gives a strong rationale for HSC
gene therapy of HIV/AIDS. Current clinical HSC gene therapy protocols (e.g. for hemoglobinopathies) involve
high-dose chemotherapy to make space in the bone marrow, and the transplantation of HSCs after ex vivo gene
transfer. Because of the risk, cost, and technical complexity, it is unlikely that ex vivo protocols will be widely
applicable, specifically in developing countries where the greatest demand for HIV/AIDS therapy lies. We have
developed an in vivo HSC transduction approach that requires only intravenous injections and could be provided
as an outpatient treatment. In this approach, HSCs are mobilized from the bone marrow into the peripheral blood
stream and transduced with intravenously injected in vivo gene transfer vectors (helper-dependent adenovirus
vectors) that target receptors present on primitive HSCs. HSCs transduced in the periphery return to the bone
marrow, persist there long-term, and contribute to all blood cell lineages. The central goal of this application is
to further develop our in vivo approach toward HIV prophylaxis and therapy with persistent eradication of HIV in
target/reservoir cells. The Specific aims are. 1. Optimize HSC mobilization regimens, HSC homing, and HDAd
vectors/expression systems to achieve i) efficient bone marrow homing of mobilized HSCs, ii) efficient trafficking
of transduced HSC progeny cells, specifically to the brain, a main HIV reservoir tissue that is difficult to target by
therapeutics, and iii) increase the level and safety of transgene expression. 2. Prevent HIV/SIV escape mutants
and eliminate virus from reservoirs by a multi-modular in vivo HSC gene therapy approach. Modules will exert
anti-HIV activity based on different mechanisms (e.g. opsonization of virus in blood by eCD4-Ig, protection of
target cells by co-receptor knockout through in vivo genome editing, and killing of infected cells independently of
MHC-I presentation by a CD4 chimeric antigen receptor (CD4-CAR) expressed on immune effector cells. 3.
Demonstrate in NHPs that the optimized in vivo HSC gene therapy approach will allow for i) complete protection
against SIV challenges (absence of escape mutants) and ii) SIV elimination in infected animals (including the
brain). Model systems to test the safety and antiviral efficacy of the approaches will include primary HSCs/HSC-
derived cells, transgenic and humanized mouse models (with and without SIV infection), as well as NHPs (in
prophylaxis and therapy setting). Our efforts will address important biological obstacles in HIV therapy in the
context of a technically simple, cost-efficient, and portable approach.

## Key facts

- **NIH application ID:** 10762991
- **Project number:** 5R01AI174304-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** HANS-PETER KIEM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $658,154
- **Award type:** 5
- **Project period:** 2023-01-10 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10762991

## Citation

> US National Institutes of Health, RePORTER application 10762991, In vivo HSC gene therapy using a multi-modular HDAd vector for HIV cure (5R01AI174304-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10762991. Licensed CC0.

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