# Identifying genetic modifiers of Sulfamidase protein stability

> **NIH NIH R03** · BAYLOR COLLEGE OF MEDICINE · 2020 · $160,500

## Abstract

PROJECT ABSTRACT
Mucopolysaccharidosis IIIA (MPS IIIA) is a devastating neurodevelopmental disorder. It is insidious in that
early neurologic development is often normal. This normal early development is typically followed by
plateauing in ascertainment of new skills followed by regression to a vegetative state and early death, often in
the second decade of life. Although there are now ongoing clinical trials of disease modifying therapies, none
are currently approved. All of these candidate therapies must overcome the blood-brain barrier for the missing
enzyme, Sulfamidase, in MPS IIIA to enter neurons and degrade glycosaminoglycans (GAGs), the storage
material that accumulates. The therapies currently being tested, most prominently viral-based gene
replacement therapy, suffer from a limited number of neurons that can be infected. Thus, even with cross-
correction between neighboring neurons, not all neurons receive an adequate quantity of Sulfamidase to
prevent their neurodegeneration. We hypothesize that increasing the stability of Sulfamidase will allow it to
accumulate in more neurons, slowing neurodegeneration and improving symptoms in patients with MPS IIIA.
We will test this hypothesis by 1) performing a cell-based genome-wide screen to identify proteins which
promote Sulfamidase degradation 2) identifying inhibition of which of these proteins increases abundance of
endogenous Sulfamidase and 3) determining which of these degradation-promoting proteins directly interact
with Sulfamidase. Through these aims, we will identify new therapeutic entry points that can be combined with
developing gene-replacement therapies for a dual therapeutic approach for this devastating disorder.

## Key facts

- **NIH application ID:** 10109897
- **Project number:** 1R03NS120078-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** JIMMY L HOLDER
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $160,500
- **Award type:** 1
- **Project period:** 2020-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10109897

## Citation

> US National Institutes of Health, RePORTER application 10109897, Identifying genetic modifiers of Sulfamidase protein stability (1R03NS120078-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10109897. Licensed CC0.

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