Thursday, September 7, 2023

Gene therapy and tazarotene/bexarotene therapy for multiple sulfatase deficiency

Promising results from research at The Jackson Laboratory (JAX) and University of Texas Southwestern Medical Center (UTSW) on a gene therapy for the ultra-rare genetic disorder, Multiple Sulfatase Deficiency (MSD), will be presented today during the WORLDSymposium, an annual research conference dedicated to lysosomal diseases. The data paves the way for a gene therapy approach for MSD patients, a very important and exciting step forward for the MSD community.

MSD is an ultra-rare genetic disorder which is often described as “Alzheimer’s in a child,” and leads to premature death, normally before 10 years of age. MSD is caused by mutations in the gene responsible for making formylglycine-generating enzyme, an essential enzyme needed by cells for normal function and to break down cellular waste products, encoded by the SUMF1 gene.

With funding provided by the United MSD Foundation, a parent-led patient advocacy organization that funds research grants for MSD studies, JAX and UTSW partnered to study the SUMf1 gene in mouse models of MSD. The research team utilized a mouse model with the SUMF1 gene “knocked out,” which has similar traits to human MSD patients. While many of the mice die soon after birth, mirroring the short lives of many children with MSD, some of the mice survived past two weeks, providing sufficient time to test possible treatments.

“The experiments were challenging given the early mortality of the mouse model and need to explore several routes of administration and doses,” said Maximiliano Presa , Ph.D., study director at The Jackson Laboratory. “These were big experiments that required a lot of effort, skill and planning by the entire team. The data are encouraging, and we are beyond delighted with the results.”

The researchers used an engineered virus (AAV9) to deliver working copies of the SUMF1 gene into the mouse cells. They tried different delivery methods, locations and time points and found that delivery of the gene through a spinal tap at seven days of age alleviated MSD symptoms. The treated mice showed wide distribution of the SUMF1 gene, no signs of toxicity or neuropathy, improved vision and cardiac function, and no behavioral deficits.

“We are thrilled with these impressive and promising results, and grateful to the scientists and supporters who made them possible,” said Amber Olsen, executive director and founder of the United MSD Foundation. “The United MSD Foundation’s mission is simple: to cure MSD, and this work represents incredible progress toward that cure. Our efforts are now focused on the critical next steps necessary to get gene therapy to children suffering and dying from MSD.”

The data supports that gene replacement therapy could be a therapeutic approach for pediatric subjects, who currently lack any treatment options, and represents a huge milestone for the MSD community.

“We are excited about the results showing successful treatment of mice with MSD, which was the result of a strong collaborative effort between investigators at UTSW, JAX and the United MSD Foundation,” said Steven Gray, Ph.D., associate professor at the University of Texas Southwestern Medical Center.

“MSD is a devastating disease and there are currently no effective treatments for patients. We are highly encouraged by the positive therapeutic response in mice and look forward to further exploring the possible use of this treatment for MSD,” said Rachel Bailey, assistant professor at the University of Texas Southwestern Medical Center.

Through the collaboration with The Jackson Laboratory, UT Southwestern and United MSD Foundation, the MSD community is one step closer to saving the lives of children impacted by this devastating disorder.

Schlotawa L, Tyka K, Kettwig M, Ahrens-Nicklas RC, Baud M, Berulava T, Brunetti-Pierri N, Gagne A, Herbst ZM, Maguire JA, Monfregola J, Pena T, Radhakrishnan K, Schröder S, Waxman EA, Ballabio A, Dierks T, Fischer A, French DL, Gelb MH, Gärtner J. Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency. EMBO Mol Med. 2023 Mar 8;15(3):e14837. doi: 10.15252/emmm.202114837. Epub 2023 Feb 15. PMID: 36789546; PMCID: PMC9994482.


Multiple sulfatase deficiency (MSD, MIM #272200) results from pathogenic variants in the SUMF1 gene that impair proper function of the formylglycine-generating enzyme (FGE). FGE is essential for the posttranslational activation of cellular sulfatases. MSD patients display reduced or absent sulfatase activities and, as a result, clinical signs of single sulfatase disorders in a unique combination. Up to date therapeutic options for MSD are limited and mostly palliative. We performed a screen of FDA-approved drugs using immortalized MSD patient fibroblasts. Recovery of arylsulfatase A activity served as the primary readout. Subsequent analysis confirmed that treatment of primary MSD fibroblasts with tazarotene and bexarotene, two retinoids, led to a correction of MSD pathophysiology. Upon treatment, sulfatase activities increased in a dose- and time-dependent manner, reduced glycosaminoglycan content decreased and lysosomal position and size normalized. Treatment of MSD patient derived induced pluripotent stem cells (iPSC) differentiated into neuronal progenitor cells (NPC) resulted in a positive treatment response. Tazarotene and bexarotene act to ultimately increase the stability of FGE variants. The results lay the basis for future research on the development of a first therapeutic option for MSD patients.

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