# Project 4: A permanent off-switch for AAV

> **NIH NIH U19** · SCRIPPS FLORIDA · 2020 · $462,500

## Abstract

PROJECT SUMMARY (Project 4 – A permanent off-switch for AAV transgenes) 
Adeno-associated virus (AAV)-expressed antibody-like entry inhibitors provide very robust protection from 
HIV-1 model viruses in rhesus macaques. AAV-mediated expression of broadly neutralizing antibodies or 
antibody-like molecules can also largely or wholly suppress an established infection in macaques. We thus 
have an effective vaccine and a pathway to drug-free virologic remission if this same approach could be 
safely applied to humans. However, there is currently no effective way to inactivate an AAV transgene in 
case of adverse events, and thus this approach is still considered too risky for most individuals. An effective 
‘off-switch’ would have two important uses. First, it would increase the safety of AAV-based vaccines and 
therapies. Second, it would facilitate eradication studies by allowing sustained expression of a potent 
antibody or entry inhibitor, and then allowing it to be inactivated so that the rate of viral rebound can be 
measured. In preliminary data, we show that a morpholino can be used together with a highly efficient 
ribozyme to induce expression of an AAV transgene. We also show that the Cre recombinase can 
permanently inactivate an AAV transgene flanked by LoxP sites. Here we proposed to combine these 
observations to generate a permanent off-switch for an AAV-expressed transgene. We will then 
demonstrate in mice that this off-switch can halt otherwise efficient expression of two potent HIV-1 entry 
inhibitors. Finally, we will use the same principles to develop a morpholino-regulated on-switch. We will 
then use this switch to test whether a 4-month delay in transgene expression from the time of AAV 
inoculation can limit immune clearance of the transgene. These studies will therefore make AAV-based 
therapeutics safer, and facilitate study of the impact of long-term antibody expression on the reservoir of 
latently infected cells.

## Key facts

- **NIH application ID:** 9891597
- **Project number:** 1U19AI149646-01
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Michael R. Farzan
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $462,500
- **Award type:** 1
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891597

## Citation

> US National Institutes of Health, RePORTER application 9891597, Project 4: A permanent off-switch for AAV (1U19AI149646-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9891597. Licensed CC0.

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