AAV-SPL, a one-time gene therapy for rare and common forms of fibrotic kidney disease - we developed adeno-associated virus mediated sphingosine phosphate lyase (AAV-SPL) as a potentially lifesaving…

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Sphinxion Therapeutics, Inc., $352,170 on September 1, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to develop and advance AAV-SPL, an adeno-associated virus gene therapy candidate for sphingosine phosphate lyase (SPL) insufficiency (SPLIS), a rare genetic kidney disease.

Sphinxion will conduct preclinical development of AAV-SPL using a novel kidney-targeting viral capsid for efficient delivery to kidney tissues. Work encompasses dose optimization, route-of-administration studies, bioavailability and durability assessments, and pilot toxicology studies in two animal species. In Aim 1, the recipient will establish the lowest effective intravenous AAV-SPL dose in a neonatal SPLIS model, targeting a mean survival of six months and a 30 percent reduction in urine albumin-to-creatinine ratio compared to untreated controls, using a virus dose below 1E13 vector genomes per kilogram. In Aim 2, the recipient will determine optimal AAV-SPL administration route in an adult SPLIS model, aiming to prevent nephropathy by achieving at least 30 percent proteinuria reduction versus untreated controls at four months post-treatment with the same dose threshold. In Aim 3, the recipient will establish bioavailability of the lowest efficacious dose across ten tissues. Performance occurs in La Jolla, California, with a period of performance through July 31, 2029.

AAV-SPL, a one-time gene therapy for rare and common forms of fibrotic kidney disease - we developed adeno-associated virus mediated sphingosine phosphate lyase (AAV-SPL) as a potentially lifesaving gene therapy for splis - an incurable genetic condition that causes kidney fibrosis and failure in childhood. AAV-SPL acts by promoting the elimination of the fibrosis-inducing lipid, sphingosine-1-phosphate and thus has potential as a one-time treatment for a broad range of fibrotic conditions. Our goal is to conduct a first-in-human clinical trial of AAV-SPL in splis, with proteinuria as the main endpoint. To that end, we will optimize dose, route, establish bioavailability and durability, and perform pilot toxicology studies in two species. In phase i, we will use a novel kidney targeting adeno-associated viral capsid to efficiently deliver AAV-SPL to kidney tissues, thereby overcoming SPL insufficiency and addressing the root cause of splis nephropathy. The lowest effective AAV-SPL dose, optimal route of administration, and bioavailability will be determined. In aim 1, we will establish the lowest effective intravenous AAV-SPL dose in the neonatal splis model, which dies within 3 weeks of birth. Milestone 1 is achieving a mean survival of six months and ³ 30% reduction in urine albumin/creatinine ratio (ACR) compared to the untreated control group with a virus dose of < 1E13 vector genomes/KG. In aim 2, we will establish the optimal route of AAV-SPL administration in a second splis model which lives to adulthood but develops nephrotic syndrome. Milestone 2 is preventing nephropathy as determined by reduction of proteinuria by at least 30% VS. Untreated controls at 4 months after treatment (by either route) with a virus dose of < 1E13 vector genomes/KG. In aim 3, we will determine AAV-SPL's bioavailability using the lowest dose that shows efficacy in aim 2 (adult model). Bioavailability will be determined in 10 tissues. Milestone 3 is raising kidney S1P lyase activity ³ 10% over vehicle control (as 10% of wild type levels correlates with protection against splis nephropathy in mice). In phase II, we will establish the durability of AAV-SPL in wild type mice using the optimal regimen determined in phase i. We will also establish the safety and bioavailability of AAV-SPL in a pilot non-human primate study. In aim 1, we will establish AAV-SPL durability by delivering IT to wild type mice using the optimal dose and route of administration followed by euthanasia and tissue harvest at 6 time points from 1 to 12 months. In aim 2, we will perform a pilot non-GLP toxicology study testing the safety of AAV-SPL in wild type mice. In aim 3, we will perform a pilot non-GLP toxicology study testing the safety, bioavailability and immunogenicity of AAV-SPL in non-human primates. Upon completion of these studies, we will have optimized AAV-SPL treatment regimen and garnered early safety, bioavailability and durability data, thus positioning US to initiate IND-enabling toxicology studies in preparation for a first-in-human clinical trial of AAV-SPL in splis.