# Developing animal models to dissociate lysosomal from inflammatory functions of acid sphingomyelinase

> **NIH NIH R03** · UNIVERSITY OF ARIZONA · 2020 · $76,750

## Abstract

Abstract
The overall goal of this proposal is to characterize the function of acid sphingomyelinase (aSMase) in sphingolipid
metabolism and pathobiology in vivo and to develop more precise enzyme replacement therapy (ERT) for
Niemann-Pick disease (NPD). ASMase catalyzes the hydrolysis of sphingomyelin (SM) to ceramide and
phosphocholine. Dysfunction of aSMase results in NPD types A and B, a lysosomal storage disorder
characterized by accumulation of sphingomyelin within the endolysosomal compartment (1). Patients with NPD-
A develop severe neurologic and visceral pathology and rarely live beyond 3 years of age (2), while patients with
NPD-B typically live to adolescence/early adulthood with no manifestation of neurological signs or symptoms (3).
Recent interest in the efforts to use aSMase proteins or plasmids for recombinant protein or DNA therapy have
been associated with increased inflammation in non-human primates (4). This is because the SMPD1 gene
which encodes aSMase, gives rise to two distinct enzymes - lysosomal sphingomyelinase (L-SMase) and
secretory sphingomyelinase (S-SMase), via differential trafficking of a common protein precursor. Our
collaborators have previously demonstrated in cells that the Ser508Ala (S508A) mutation in aSMase
(aSMaseS508A) retains L-SMase activity but is defective in S-SMase (5). Furthermore, we have demonstrated that
loss of S-SMase activity in cells expressing the aSMaseS508A mutant prevents chemokine amplification by pro-
inflammatory cytokines (6). Previous work has demonstrated that mice expressing an aSMase fusion protein
that retained L-SMase activity exhibited protection of the cerebellar Purkinje cell layer and were protected from
the severe neurologic disease observed aSMase deficient mice (7). Therefore, careful determination of the in
vivo function of the S508A mutant may allow its development as effective ERT (or gene replacement) devoid of
inflammatory effects.
 Building on these data, our lab has generated a novel genetically modified mouse model (GEMM) containing
the S508A point-mutation in SMPD1. This GEMM, aSMaseS508A, was generated in collaboration with Jackson
Laboratories using CRISPR–Cas9 technology. Our preliminary data in these mice demonstrate complete loss of
S-SMase activity in serum.
Therefore, the goals of this proposal are innovative and significant as this will be the first study to directly
define the role of this SMPD1 variant in vivo, defining the effects of this mutation on sphingolipid
metabolism, pathology, and symptoms of NPD. To this end, we propose the following specific aims:
Specific Aim 1. Establish the effects of the aSMaseS508A mutations on sphingolipid metabolism in vivo.
Specific Aim 2. Define the effects of aSMaseS508A on NPD pathobiology in vivo.

## Key facts

- **NIH application ID:** 9975866
- **Project number:** 5R03HD099467-03
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Ashley Jones Snider
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $76,750
- **Award type:** 5
- **Project period:** 2020-04-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975866

## Citation

> US National Institutes of Health, RePORTER application 9975866, Developing animal models to dissociate lysosomal from inflammatory functions of acid sphingomyelinase (5R03HD099467-03). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9975866. Licensed CC0.

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