# AAV capsid engineering for enhancing gene transfer

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $713,439

## Abstract

Recombinant AAV vectors have shown great promise in clinical trials. These vectors represent a gene
transfer/genome editing platform that has the potential to treat not only genetic diseases but a myriad of
acquired disorders that include infection and infection prophylaxis, neurodegeneration, and diseases resulting
from immune system dysfunction. One of the major rate-limiting steps in translating the success achieved in
animal models of human disease to humans is the lack of a strong correlation between vector transduction
properties between species. Because transduction is dictated in large part by variations in the capsid protein
sequence, in order to obtain capsids with enhanced transducing properties in humans we have pursued multi-
species capsid shuffling, and in vitro and in vivo evolutionary selection paradigms to create and identify novel
chimeric capsids with clinically relevant assets. During the current funding period, we discovered several
chimeric capsids with a 10-fold increased primate liver transduction profile. One of these capsids is in clinical
trials, and two more recent isolates are in late preclinical testing by commercial and academic centers. Yet
even these improved AAV vectors do not appear to reach the same level of transduction that can be achieved
in rodents with other established AAV capsids. Thus, the general goal of the proposed work is to build upon
our efforts to develop high throughput technologies for new capsid engineering approaches, and optimized
selection schemes. Our specific goals are to create and identify capsids that have enhanced: (1) human liver
transduction, (2) penetration through the human blood brain barrier and transduction of neurons and
astrocytes, and (3)transduction of human hematopoietic stem cells for increased genome editing efficiencies.
We will also study the mechanism behind the species selectivity observed with several of our new specific
chimeric capsid derived vectors. The vectors that are obtained in the respective screens will be further
evaluated in either an appropriate humanized animal model or non-human primates. The information learned
will contribute to our knowledge towards optimizing AAV-mediated gene transfer in humans. The new capsids
will be made available for use in clinical gene transfer/genome editing trials.

## Key facts

- **NIH application ID:** 9997583
- **Project number:** 2R01AI116698-06
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Mark A Kay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $713,439
- **Award type:** 2
- **Project period:** 2015-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997583

## Citation

> US National Institutes of Health, RePORTER application 9997583, AAV capsid engineering for enhancing gene transfer (2R01AI116698-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9997583. Licensed CC0.

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