# Optimizing AAV Vectors for Central Nervous System transduction

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $526,679

## Abstract

Project Summary
Mucopolysaccharidosis (MPS) IIIB is a neurodegenerative lysosomal storage disease (LSD) caused by deficient
degradation of heparan sulfate. Clinically this manifests as cognitive decline, developmental regression, impaired
mobility and ultimately premature death. There are currently no effective therapies. Due to the neurodegenerative
nature of this disease, optimal CNS transduction is necessary for human trials. Several groups have
demonstrated improvement of the mouse model using different adeno-associated viral (AAV) vectors. We have
recently demonstrated that AAV8 has better brain gene delivery in MPS IIIB than wild type mice. A similar finding
of altered brain delivery in Sly Syndrome compared to wild type mice has been published for AAV9. However,
for translation to human trials, it is essential to identify a highly effective AAV capsid serotype which will deliver
to cells in the requisite brain regions. More generally, for any treatment of human neurologic disease in which
the central nervous system (CNS) is of substantially larger volume and is phylogenetically distant compared to
our current mouse models, we will need to identify an optimal vector and delivery method for CNS approaches.
To this end, we have developed a novel two-step bar code AAV vector system that allows assessment of multiple
AAV vector serotypes within the same animal, greatly reducing the number of animals needed for statistical
comparisons of brain delivery. This system has a genetic bar code that identifies each vector and a second bar
code that is incorporated during PCR amplification of each brain region isolated. The bar code system allows
determination of distribution and the expression levels of each serotype in anatomical areas of interest. We will
use this novel two-step barcoded AAV vector system to simultaneously identify brain delivery of 40 AAV
serotypes and capsid variants in wild type and MPS IIIB mice as well as in non-human primates - the closest to
human model available to us. We will identify whether injections into the body of the brain or the less invasive
injection into the fluid around the brain method provides a better vector distribution. We will identify which wild-
type AAV serotypes or capsid mutants provide the best delivery by region, are altered by presence of the disease,
and are similar between primate and mouse models. The results will inform clinical trial vector selection across
the spectrum of central neurologic disorders, including MPS III. Subsequently, our MPS IIIB gene construct will
be packaged into the optimal vector to assess treatment effect in MPS IIIB mice. We hypothesize that CNS
transduction and distribution will differ by serotype and species and that some serotypes will transduce differently
between wild type and Sanfilippo Syndrome mice. Our specific aims are therefore:
1. We will determine the brain delivery of AAV serotypes in non-human primates (NHP) and in wild type and
 MPS IIIB affected mice. W...

## Key facts

- **NIH application ID:** 9930160
- **Project number:** 5R01NS102624-04
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Coy D Heldermon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $526,679
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930160

## Citation

> US National Institutes of Health, RePORTER application 9930160, Optimizing AAV Vectors for Central Nervous System transduction (5R01NS102624-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9930160. Licensed CC0.

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