Characterizing the natural history of sphingosine phosphate lyase insufficiency syndrome (SPLIS): a fundamental step in the development of a targeted cure for this novel atypical sphingolipidosis

Summary Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is an ultra-rare, devastating, often lethal inborn error of metabolism recognized just five years ago. Most affected children exhibit a rapidly progressive form of nephrotic (protein spilling) syndrome which leads to kidney failure, the main cause of death. Affected children

may also exhibit adrenal insufficiency, hypothyroidism, skin and neurological defects, and immunodeficiency. Although kidney transplantation may 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 is a member of a new family of non-lysosomal sphingolipid disorders about which relatively little is known. Despite the dismal outcome in SPLIS, targeted therapies are rapidly being developed. Some children with milder forms

of the condition 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 a universal and potentially curative treatment for SPLIS. Clinical trials testing these two therapeutic

strategies are on the horizon. Although we have made rapid progress in methods of SPLIS patient finding, biomarker development, and therapeutics, achieving two additional goals will enhance our readiness to undertake SPLIS clinical trials: a) providing a comprehensive understanding of the natural history of SPLIS

including the full spectrum of clinical presentations, disease subgroups, and natural progression; b) developing a method to identify SPLIS patients before irreversible kidney damage has occurred. We are now in a pivotal position to achieve both these strategic goals. We hypothesize that specific disease features and biomarkers

will predict quality of life and survival in SPLIS patients. To confirm our hypothesis and achieve our goals, we propose three Aims: 1) Characterize the spectrum of SPLIS clinical presentations and their natural progression over time; 2) Determine how biomarker endpoints reflect or predict functional change over time in SPLIS

patients; 3) Establish a screening strategy for early detection of SPLIS based on blood S1P levels. In achieving these Aims, we will develop a deeper understanding of the spectrum, sequence, and timing of onset of SPLIS manifestations, and will identify predictors of disease outcomes that are meaningful to patients and families

and that will be critical for patient selection for clinical trial enrollment. Our project will create useful tools for measuring outcomes in SPLIS, providing quantifiable endpoints to be used in clinical trials. Overall, revealing the natural history of SPLIS will lay the foundation for evaluating the impact of targeted interventions in clinical

trials. Developing early detection methods will open a therapeutic window in which treatments to prevent death and the need for kidney transplantation can be administered. Creation of biospecimen collections and stem cell lines will facilitate deeper investigation into the pathophysiology of SPLIS and its related sphingolipid disorders.