# In Vivo Gene Editing of B cells with NICE-AAV Vectors

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2024 · $770,685

## Abstract

ABSTRACT
HIV-specific gene therapies are a powerful and promising means to achieve HIV cure/stable remission in the
absence of antiretroviral therapy (ART). Broadly neutralizing antibodies (bNAbs) and analogous molecules such
as eCD4-Ig offer one of the clearest paths to a cure, but are hindered by three key obstacles. First, passive
administration of bNAb/eCD4-Ig proteins is by definition a transient therapy; when circulating levels of these
potent anti-HIV factors decline, virus replication is able to resume. Second, gene therapy vector-based
approaches including adeno-associated virus (AAV) support prolonged expression of bNAbs and other antiviral
transgenes, but are frequently limited by host immune responses. Third, potent ART regimens suppress viral
replication to extremely low levels, rendering engineered HIV-specific lymphocytes unable to recognize and clear
persistently infected cells. We have generated an exciting set of tools and preliminary data that directly addresses
each of these barriers. To overcome the transient nature of bNAbs and associated immunogenicity of vectored
delivery approaches, we have performed an in vivo screen in nonhuman primates (NHP) and identified
engineered AAV variants that persist long term (consistent with a lack of recognition by the host immune system),
and specifically target B cells. B cell tropic vectors will be packaged with CRISPR-Cas9 gene editing machinery,
applying highly innovative covalent linkage methodology to double our vectors’ packaging capacity. We refer to
our novel in vivo delivery approach as Non-Immunogenic, Cargo-Enhanced (NICE) AAV: in a single dose, NICE-
AAV vectors will specifically reprogram B cells with bNAb or eCD4-Ig sequences targeted to the native IgG locus.
Finally, we will overcome the significant problem of insufficient viral antigen by supplying cell-associated HIV-1
Env in trans. Our recent publication in the NHP model demonstrates the immense success of this strategy to
stimulate HIV-1-specific chimeric antigen receptor (CAR) T cells and should similarly boost and trigger expansion
of our gene-edited B cells. The central goals of our proposal are to validate the efficiency and specificity of B
cell-targeted NICE-AAV (AIM 1), to demonstrate that this in vivo delivery approach enables persistent
bNAb/eCD4-Ig expression in HIV anatomical compartments and reservoir sites (AIM 2), and most importantly,
to achieve a therapeutic impact in humanized mouse and NHP models of HIV persistence (AIM 3). We will merge
one of the most promising therapeutic modalities for HIV cure (bNAbs/eCD4-Ig) with our extremely unique in
vivo delivery platform (NICE-AAV). Importantly, this approach will be applicable not only for HIV-1, but for the
broad range of pathologies where monoclonal antibody therapies offer clinical benefit.

## Key facts

- **NIH application ID:** 10745971
- **Project number:** 5R01AI167004-04
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Christopher W Peterson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $770,685
- **Award type:** 5
- **Project period:** 2021-12-16 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10745971

## Citation

> US National Institutes of Health, RePORTER application 10745971, In Vivo Gene Editing of B cells with NICE-AAV Vectors (5R01AI167004-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10745971. Licensed CC0.

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