# Interrogation of retroelement-derived proteins for functional gene transfer

> **NIH NIH F31** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2022 · $42,689

## Abstract

Project Summary and Abstract
Gene therapy enables the treatment of a large number of genetic diseases through delivery of nucleic acids striking at the
root of the disease. This is advantageous because it is highly modular, allowing for a number of different cargo nucleic
acids to be delivered depending on the disease cause. As such, the ideal gene therapy delivery vector would be able to
carry a variety of cargo, deliver this in a targeted manner, and accommodate a range of cargo sizes. There are a number of
techniques utilized to deliver nucleic acids including viral systems like adenovirus, adeno-associated virus (AAV), and
lentivirus, as well as non-viral methods including nanoparticles. Although these therapies can be successful, a key
limitation to currently used vectors is the immune response which can lead to ineffective delivery of nucleic acid cargo.
There is currently a need to develop effective and non-immunogenic delivery vehicles for gene therapy for a wide range of
diseases, including neurological disease, for which effective delivery vehicles have yet to be designed.
To this end, mammalian genomes contain numerous virus-like genes, some of which have been co-opted by their host
cells for important functions. Among these are homologs of gag, which encodes the capsid protein. We hypothesize that
endogenous genes encoding a capsid domain have the ability to self-assemble into capsids and mediate intercellular
communication by binding, secreting, and delivering nucleic acid cargos. We propose to explore and re-engineer
endogenous capsid-containing proteins for use as gene therapy vectors. We hypothesize that delivery vehicles composed
entirely of self proteins will be more effective than standard vectors as they could be non-immunogenic. Here we propose
to use an approach combining in vitro characterization, re-engineering, and in vitro and in vivo validation to identify
candidate proteins and learn how they can be re-engineered. These systems will ideally be modular, having both
programmable cargo and tropism to treat a range of diseases. We hope that by identifying and re-engineering these
systems, the resulting fully endogenous delivery vehicle will be useful for efficient, reprogrammable, and
non-immunogenic gene delivery.
With the goal of becoming an independent investigator, this project will also support development of computational
biology skills, molecular biology expertise as well as mentorship and scientific communication skills. These will be
supported by the excellent research environment at the Broad Institute and MIT.

## Key facts

- **NIH application ID:** 10537044
- **Project number:** 1F31CA275339-01
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Blake Lash
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $42,689
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10537044

## Citation

> US National Institutes of Health, RePORTER application 10537044, Interrogation of retroelement-derived proteins for functional gene transfer (1F31CA275339-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10537044. Licensed CC0.

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