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

Piming Zhao,Joanna Y Lee,Gizachew B Tassew,Yingbao Yang,Jen-Yeu Wang,Sarah King,Nancy Keller,Julie D Saba,Babak Oskouian,Ronald M Krauss,Jinghui Luo,Jeffrey B Hodgin,Gordon L Watson,Denise P Muñoz,Felicia Tang

doi:10.1172/jci.insight.145936

Abstract

Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a rare metabolic disorder caused by inactivating mutations in sphingosine-1-phosphate lyase 1 (SGPL1), which is required for the final step of sphingolipid metabolism. SPLIS features include steroid-resistant nephrotic syndrome and impairment of neurological, endocrine, and hematopoietic systems. Many affected individuals die within the first 2 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 proinflammatory and profibrogenic cytokines observed in KO kidneys were attenuated by treatment. Plasma and tissue sphingolipids were reduced in treated compared with 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.

Highlights

Biallelic loss-of-function mutations in sphingosine-1-phosphate lyase 1 (SGPL1) result in sphingosine-1phosphate lyase insufficiency syndrome (SPLIS), a rare metabolic disorder associated with nonlysosomal sphingolipid storage [1, 2]
Human WT SGPL1 cDNA or a self-cleaving bicistronic system for coexpressing red fluorescent protein (RFP) and sphingosine phosphate lyase (SPL) were cloned in an AAV2 vector under control of the CMV promoter
Of the main disease features, steroid-resistant nephrotic syndrome (SRNS) leading to rapid development of end-stage renal disease and progressive neurological deterioration are responsible for most SPLIS-associated deaths, and adrenal insufficiency is highly consequential

Summary

Introduction

Biallelic loss-of-function mutations in sphingosine-1-phosphate lyase 1 (SGPL1) result in sphingosine-1phosphate lyase insufficiency syndrome (SPLIS), a rare metabolic disorder associated with nonlysosomal sphingolipid storage [1, 2]. Most affected individuals exhibit steroid-resistant nephrotic syndrome (SRNS) progressing rapidly to end-stage renal disease. Nephrosis is most often associated with focal segmental glomerulosclerosis pathology, including the aggressive collapsing variant. Primary adrenal insufficiency is the second most common feature. Defects of the central and peripheral nervous systems, which may include developmental delay or regression accompanied by characteristic findings on magnetic resonance imaging, occur with other disease features or independently in about half of cases [1, 11]. T cell lymphopenia seems to be a universal feature, some level of T cell function usually persists. No specific therapies for the treatment of SPLIS have been established

Methods

Results

Conclusion