In vivo gene editing of b cells with nice-AAV vectors
Active Project Grant Awarded Last action
- Award ID
- R01AI167004
- Recipient
-
Fred Hutchinson Cancer Center UEI TJFZLPP6NYL6
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $3,834,765
Award facts
- Assistance listing
- 93.242 Mental Health Research Grants
- Completion date 98% complete
- Place of performance
- Seattle, WA 98109, USA
Award details come from USAspending.gov.
Description
- 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.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $125,000 | |
| Amendment | $125,000 | |
| Amendment | $125,000 | |
| Amendment | $125,000 | |
| Amendment | $605,441 | |
| Amendment | $12,500 | |
| Amendment | $64,569 | |
| Amendment | $112,500 | |
| Amendment | $112,500 | |
| Amendment | $112,500 | |
| Amendment | $125,000 | |
| Amendment | $125,000 | |
| Amendment | $646,804 | |
| Amendment | $646,804 | |
| Amendment | $125,000 | |
| Amendment | -$138,724 | |
| Amendment | $138,724 | |
| Amendment | $138,724 | |
| Amendment | -$138,724 | |
| Amendment | -$138,724 | |
| Amendment | $138,724 | |
| Amendment | $125,000 | |
| Amendment | $337,111 | |
| Amendment | $125,000 | |
| Amendment | $125,000 | |
| Amendment | -$125,000 | |
| Amendment | -$337,111 | |
| Amendment | -$337,111 | |
| Amendment | -$125,000 | |
| Amendment | $125,000 | |
| Amendment | $608,258 | |
| Original award | $125,000 |
Show all 32
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| University Of Washington | $137,325 | |
| Medizinische Hochschule Hannover (Mhh) | $150,362 | |
| Medizinische Hochschule Hannover (Mhh) | $143,399 | |
| University Of Washington | $60,775 |
Quick answers
Who received award R01AI167004?
R01AI167004 was awarded to Fred Hutchinson Cancer Center by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on December 16, 2021.
How much is award R01AI167004 worth?
$3,834,765 has been obligated on R01AI167004.
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