# Gene Transfer and NMR Studies in Alpha-Mannosidosis Brain

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $709,492

## Abstract

A major barrier to effective treatment of the central nervous system (CNS) in most inherited lysosomal
storage diseases (LSD) is that the metabolic defect in all brain cells results in widespread pathology. The
therapeutic principle for most LSDs is to transfer a normal enzyme cDNA into a subset of diseased cells,
thereby correcting both vector-transduced cells and neighboring non-transduced cells that take up the secreted
therapeutic enzyme. To achieve global correction, transduced cells must be dispersed 3-dimensionally
throughout the brain so that secreted vector-encoded therapeutic enzyme can reach all non-transduced cells.
Although intravascular injection of certain AAV vector serotypes can cross the blood-brain barrier and deliver
genes widely in rodent brains, AAV vector distribution in large mammals occurs mostly in the lower brain and
spinal cord, limiting the potential for treatment. Thus, optimization of vector distribution in large animal models
of human diseases is critically needed to facilitate translation into clinical usage.
 In the prior grant period, we have shown that a novel AAV serotype (AAV.hu32) mediates widespread
gene delivery in a cat model of alpha-mannosidosis (AMD) caused by a mutation in the gene encoding
lysosomal a-mannosidase (MANB) that recapitulates the severe form of AMD. Notably, high doses of
AAV.hu32 encoding MANB resulted in global correction of the storage lesions and improvements in disease
parameters. Although this appears promising for translation into clinical usage, the vector doses required
would be near the limits of production for clinical grade AAV vector when scaled up to human patients and
there have been safety concerns raised in recent clinical trials for use of such high vector doses. Finally, new
preliminary data shows that vector doses that are completely effective when AMD cats are treated in the early
stages of the disease do not mediate complete brain correction when treatment is initiated at a more advanced
stage of disease, providing additional impetus to improve global brain delivery at lower vector doses.
 In exciting new studies, we have found that injection via carotid artery was even more effective than
intravenous injection, suggesting that passage of concentrated virus through the vascular bed of the brain
improves uptake. Surprisingly, we also found that while direct injection of AAV.hu32 into brain parenchyma
transduced oligodendrocytes, astrocytes and neurons, its vascular delivery resulted in the almost exclusive
transduction of neurons. Thus, current studies will focus on reducing the required vector dose by determining
the route the vector takes between blood and brain to specifically transduce neurons, increasing the levels of
MANB produced by the genetically corrected neurons, and increasing the number of transduced cells by an
alternative dosing regimen that will maximize vector uptake in the vascular bed of the brain. We will then
determine if an optimized combination...

## Key facts

- **NIH application ID:** 10897727
- **Project number:** 5R01DK063973-17
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** JOHN H WOLFE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $709,492
- **Award type:** 5
- **Project period:** 2002-09-03 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897727

## Citation

> US National Institutes of Health, RePORTER application 10897727, Gene Transfer and NMR Studies in Alpha-Mannosidosis Brain (5R01DK063973-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10897727. Licensed CC0.

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