# Ganglioside Replacement Therapy for GM3 Synthase Deficiency

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $195,138

## Abstract

Project Abstract
Gangliosides are complex sialic acid-containing glycosphingolipids that are particularly enriched in the brain and
are critical for brain development and function. GM3 synthase deficiency is a genetic disorder of ganglioside
biosynthesis occurring primarily, but not exclusively, in the Old Order Amish. GM3, which the patients cannot
synthesize, is itself not abundant in the brain; rather, it serves as the common precursor for all downstream
gangliosides. Thus, patients completely lack cell-surface gangliosides. Appearing normal at birth, patients
developmentally stagnate within a few months. They suffer from intractable seizures and cannot sit, stand, walk,
talk, see, or hear. There is an immediate need to develop therapies for this disorder. We hypothesize that
ganglioside replacement therapy represents an effective treatment strategy than can be immediately leveraged
clinically. GM1 is one of the four major brain ganglioside species synthesized from GM3. There have been
multiple clinical trials testing exogenous GM1 for the treatment of aging-related diseases such as Parkinson’s
disease, stroke, and Alzheimer’s, for which depletion of GM1 is a common feature. These trials have shown
GM1 therapy to be safe in humans. Here, we have partnered with La Jolla Pharmaceuticals who will provide
semisynthetic GM3 and GM1 for pre-clinical testing. Aim 1 will compare the two species head-to-head for their
ability to repopulate cell-surface gangliosides in a patient-derived neural crest cell line and in GM3 synthase
knockout mice in vivo. While we hypothesize that GM1 will be superior to GM3 in this regard, whichever species
demonstrates the best normalization of cell-surface gangliosides will be tested as a therapeutic agent in Aim 2.
Aim 2 will be a longitudinal study in which ganglioside-deficient mice will be treated either at birth or at weaning
with exogenous ganglioside delivered intracerebrally; the mice will be followed in a survival study with periodic
neuromotor function testing. Altogether, the deliverables for this project will include: 1) a biochemical evaluation
of GM1 versus GM3 for ganglioside repopulation and brain distribution; 2) the optimization of intracerebral
ganglioside dosing (slow release vs. bolus injection); 3) an assessment of placental ganglioside transfer in vivo;
4) determination of the turnover rate of exogenous gangliosides in vivo; and 5) an evaluation of the therapeutic
benefits of ganglioside replacement in a clinically-relevant mouse model. In summary, this high-risk R21 project
may produce an immediate high-reward in the form of the pre-clinical evidence needed to fast-track ganglioside
replacement therapy for the treatment of human genetic ganglioside deficiencies. Further, data from this project
will fuel a future R01 proposal designed to optimize the route of delivery (peripheral versus central) and to test
multimodal efficacy of ganglioside therapy with gene therapy.

## Key facts

- **NIH application ID:** 9932469
- **Project number:** 5R21HD097403-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** ERIC S GOETZMAN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $195,138
- **Award type:** 5
- **Project period:** 2019-05-20 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932469

## Citation

> US National Institutes of Health, RePORTER application 9932469, Ganglioside Replacement Therapy for GM3 Synthase Deficiency (5R21HD097403-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9932469. Licensed CC0.

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