# Proof-of-concept for the use of enzyme replacement therapy as a lifesaving treatment for sphingosine phosphate lyase insufficiency syndrome

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $463,150

## Abstract

PROJECT SUMMARY
SPLIS is an ultra-rare, often lethal inborn error of metabolism recognized just five years ago. Most affected
children exhibit a rapidly progressive form of nephrotic syndrome which leads to failure-to-thrive and kidney
failure, the main cause of death. Affected children may exhibit adrenal insufficiency, hypothyroidism, skin and
neurological defects, and immunodeficiency. Although kidney transplantation can be lifesaving, there is no cure
for SPLIS. SPLIS is caused by recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P)
lyase, a vitamin B6-dependent enzyme responsible for catabolism of the bioactive lipid S1P in the final step of
sphingolipid metabolism. SPLIS-associated SGPL1 mutations impair S1P lyase activity, enzyme localization
and/or stability, and cause sphingolipid accumulation leading to multi-organ dysfunction and failure. Unlike
classical sphingolipid metabolic disorders involving lysosomal enzymes (such as Tay-Sachs disease), SPLIS is
an atypical (non-lysosomal) sphingolipid disorder. The study of SPLIS biology is revealing shared features of
atypical sphingolipid disorders and the potential for common diagnostic, monitoring and treatment strategies.
As pioneers in the field —having identified the first S1P lyase gene from budding yeast and studied its function
for decades—we are now directing our expertise to develop targeted therapies for SPLIS. To our knowledge,
we are the only group working toward that goal. Some children with less severe forms of SPLIS may respond
to supplementation with vitamin B6, the enzyme’s cofactor. Studies in a mouse model of SPLIS have provided
proof-of-concept for the use of adeno-associated virus-mediated SGPL1 gene therapy as potentially curative
treatment for SPLIS. Clinical trials testing these two therapeutic strategies are in the planning stages. Further,
we have developed disease biomarkers and are preparing to launch the first prospective SPLIS natural history
study. However, there are major challenges to existing interventions. Pyridoxine is only useful for a limited
number of patients harboring B6-responsive variants. Kidney transplantation requires adequate weight gain, is
costly, and has high morbidity. Gene therapy is irreversible, can have severe toxicities, and cannot be used
prenatally. We hypothesize that enzyme replacement therapy (ERT) represents a lifesaving treatment for
SPLIS that acts by preserving kidney function and offers many advantages over other treatment strategies. In
this project we will use two powerful and complementary mouse models of SPLIS, a well-established knock-out
mouse and a novel knock-in mouse, to test our hypothesis with two specific aims: 1) Establish proof-of-concept
for ERT as a lifesaving treatment for SPLIS; 2) Establish proof-of-concept for the ability of ERT to prevent or
reverse SPLIS nephrosis. Our results will provide the rationale for further developing ERT as a treatment for
SPLIS. Our team, comprised of an exp...

## Key facts

- **NIH application ID:** 10938964
- **Project number:** 1R21TR005157-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** JULIE D SABA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $463,150
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10938964

## Citation

> US National Institutes of Health, RePORTER application 10938964, Proof-of-concept for the use of enzyme replacement therapy as a lifesaving treatment for sphingosine phosphate lyase insufficiency syndrome (1R21TR005157-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10938964. Licensed CC0.

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