Efficacy of AAV9-mediated SGPL1 gene transfer in a mouse model of S1P lyase insufficiency syndrome

Abstract

Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a rare metabolic disorder caused by inactivating mutations in SGPL1, which is required for the final step of sphingolipid metabolism. SPLIS features include steroid-resistant nephrotic syndrome (SRNS) and impairment of neurological, endocrine, and hematopoietic systems. Many affected individuals die within the first two years. No targeted therapy for SPLIS is available. We hypothesized that SGPL1 gene replacement would address the root cause of SPLIS, thereby serving as a universal treatment for the condition. As proof of concept, we evaluated the efficacy of adeno-associated virus 9-mediated transfer of human SGPL1 (AAV-SPL) given to newborn Sgpl1 KO mice that model SPLIS and die in the first weeks of life. Treatment dramatically prolonged survival and prevented nephrosis, neurodevelopmental delay, anemia, and hypercholesterolemia. STAT3 pathway activation and elevated pro-inflammatory and pro-fibrogenic cytokines observed in KO kidneys were attenuated by treatment. Plasma and tissue sphingolipids were reduced in treated compared to untreated KO pups. SGPL1 expression and activity were measurable for at least 40 weeks. In summary, early AAV-SPL treatment prevents nephrosis, lipidosis and neurological impairment in a mouse model of SPLIS. Our results suggest that SGPL1 gene replacement holds promise as a durable and universal targeted treatment for SPLIS.

Sphingosine Phosphate Lyase Is Upregulated in Duchenne Muscular Dystrophy, and Its Inhibition Early in Life Attenuates Inflammation and Dystrophy in Mdx Mice

“…In the future, studies conducted over longer time periods will be required to establish the true potential of SPL inhibition as a strategy to mitigate muscular dystrophy. This is particularly important in consideration of the upregulated inflammatory cytokines observed in global Sgpl1 knockout mice [ 27 , 29 ]. Encouragingly, our transcriptional profiling showed a suppression of STAT activation and chemokine signaling and no obvious upregulation of cytokines in LX2931-treated subjects.…”

Outcomes of progranulin gene therapy in the retina are dependent on time and route of delivery

“…While it has been shown that systemic injections with AAV9 in neonatal mice leads to the production of anti-AAV9 antibodies, another study has reported that systemic delivery to neonatal mice (P2) does not lead to the production of antibodies against their transduced protein of interest (factor VIII protein expressed in mice that model hemophilia A). 29,30 The analysis of an immune response specific to PGRN is necessary, as the identification of an adaptive immune response to the protein after systemic and intravitreal delivery warrants further study. Moreover, the question of clinical translatability arises when retinal thickness improvement was only seen after systemic delivery in neonates.…”

Advances in mouse genetics for the study of human disease

“…These include the treatment of recessive genetic disorders where gene replacement strategies can be employed to restore gene function. A knock-out of the Sgpl1 gene was employed to investigate the efficacy of an Adeno-associated virus (AAV) therapeutic strategy for S1P lyase insufficiency syndrome ( 82 ). AAV9-mediated transfer of human Sphingosine-1-phosphate lyase 1 (SGPL1) delivered to newborn Sgpl1 knockout (KO) mice, which normally die in the first few weeks of life, led to prolonged survival and ameliorated pathology, including neurodevelopmental delay, anaemia and hypercholesterolaemia.…”