Kidney Week

Abstract: TH-PO0616

Cell-Specific Evaluation of AAV9-Mediated SGPL1 Gene Delivery in a Sgpl1-/- Mouse Model with Nephrotic Syndrome

Session Information

• Monogenic Kidney Diseases: Glomerular
  November 06, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases

Authors

• Lomjansook, Kraisoon, Department of Pediatrics, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Kraisoon Lomjansook, MD

• Franken, Gijs AC, Department of Pediatrics, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Gijs AC Franken, MS, MSc, PhD

• Lemberg, Katharina, Department of Pediatrics, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Katharina Lemberg, MD

• Saida, Ken, Department of Pediatrics, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Ken Saida, MD, PhD

• Marchuk, Daniel, Department of Pediatrics, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Daniel Marchuk, MD

• Zion, Elena, Department of Pediatrics, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Elena Zion, MD

• Prakash, Chiranth M, Department of Pediatrics, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Chiranth M Prakash, PhD

• Riedhammer, Korbinian M., Department of Pediatrics, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Korbinian M. Riedhammer, MD

• Nelson, Becca, Department of Pediatrics, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Becca Nelson

• Buerger, Florian, Department of Pediatrics, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Florian Buerger, MD, PhD

• Saba, Julie D., Department of Pediatrics, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California, United States

Julie D. Saba, MD, PhD

• Hildebrandt, Friedhelm, Department of Pediatrics, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Friedhelm Hildebrandt, MD

Group or Team Name

• Hildebrandt Lab.

Background

Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is an autosomal recessive disorder caused by mutations in SGPL1, leading to deficient sphingosine-1-phosphate lyase 1 (S1P lyase) activity which essential for sphingolipid catabolism, and its deficiency commonly results in nephrotic syndrome and primary adrenal insufficiency. Currently, no targeted therapy exists. However, gene replacement therapy (GRT) using adeno-associated virus (AAV) vector has shown promise in extending survival and ameliorating neurological and immunological deficits. In this study, we evaluated the efficacy of GRT in Sgpl1^-/- mouse model using immunofluorescence analysis.

Methods

We used the Sgpl1^-/- mouse model and administered AAV9 that expresses human SGPL1 under a universal promoter (AAV9-CAG-hSGPL1), in accordance with the previously published method (Int J Mol Sci. 24:15560, 2023). 1-day-old neonatal mice received 2.5-3 × 10¹⁴ gc/kg AAV9-CAG-hSGPL1 via retro-orbital (RO) or intrarenal (IR) injection. Albuminuria was measured weekly until death. To evaluate tissue-specific transduction, AAV9-CAG-hSGPL1 was co-injected with AAV9-CAG-tdTomato (1:2 ratio). At 12–14 days post-injection, tissues (kidney, liver, adrenal gland, brain, spleen) were harvested and processed for immunofluorescence of paraffin-embedded sections to assess cellular transduction.

Results

AAV9-CAG-hSGPL1 significantly improved median survival from 3–4 weeks to 100 days, with some mice surviving up to 7.5 months. There was no significant difference in survival between RO and IR (median 101 and 74 days, P=0.807). Albuminuria onset was delayed from 2 to 14 weeks of age. Immunofluorescence revealed transduction of hepatocytes (28%), adrenal x-zone cells (45%), and cerebellar Purkinje cells (12%) in all mice (N=8). We are currently evaluating percent podocyte transduction with the question, whether renal transduction was limited, shown in only 2 mice (1 RO, 1 IR).

Conclusion

We reproduced a partial rescue of SPLIS by AAV9-CAG-hSGPL1 GRT, significant prolonging survival and delaying nephrotic onset in Sgpl1^-/- mice. Phenotypic improvements may be either due to hSGPL1 expression by renal or extrarenal expression causing phenotypic rescue by available S1P lyase.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.20258hk03bfw