In this issue of Molecular Therapy, Pham and colleagues describe the promising preclinical development of a lentiviral-modified hematopoietic stem cell (HSC) therapy for multiple sulfatase deficiency (MSD), a lysosomal storage disorder. MSD presents unique challenges for therapy development. MSD impacts several lysosomal enzymes, yet the responsible gene, SUMF1, does not itself encode a lysosomal enzyme. Rather, it encodes formylglycine-generating enzyme (FGE), which resides in the endoplasmic reticulum and is crucial for the post-translational modification of multiple sulfatases that are essential for the degradation of sulfatides, glycosaminoglycans, and other substrates inside the lysosome. While the delivery of soluble lysosomal proteins is feasible with therapeutic modalities such as enzyme replacement therapy, gene therapy, and HSC transplantation, there has not been an obvious path forwards for MSD, in which multiple lysosomal enzymes would need to be “replaced.” This complexity has historically made MSD a difficult condition to target with conventional approaches. As a result, while significant progress has been made in the development of therapies for numerous lysosomal storage diseases, families affected by MSD have often felt left on the sidelines, lacking effective options.
Pham V, Tricoli L, Hong X, Wongkittichote P, Castruccio Castracani C, Guerra A, Schlotawa L, Adang LA, Kuhs A, Cassidy MM, Kane O, Tsai E, Presa M, Lutz C, Rivella SB, Ahrens-Nicklas RC. Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of multiple sulfatase deficiency. Mol Ther. 2024 Nov 6;32(11):3829-3846. doi: 10.1016/j.ymthe.2024.08.015. Epub 2024 Aug 22. PMID: 39169621; PMCID: PMC11573602.
Abstract
Multiple sulfatase deficiency (MSD) is a severe, lysosomal storage disorder caused by pathogenic variants in the gene SUMF1, encoding the sulfatase modifying factor formylglycine-generating enzyme. Patients with MSD exhibit functional deficiencies in all cellular sulfatases. The inability of sulfatases to break down their substrates leads to progressive and multi-systemic complications in patients, similar to those seen in single-sulfatase disorders such as metachromatic leukodystrophy and mucopolysaccharidoses IIIA. Here, we aimed to determine if hematopoietic stem cell transplantation with ex vivo SUMF1 lentiviral gene therapy could improve outcomes in a clinically relevant mouse model of MSD. We first tested our approach in MSD patient-derived cells and found that our SUMF1 lentiviral vector improved protein expression, sulfatase activities, and glycosaminoglycan accumulation. In vivo, we found that our gene therapy approach rescued biochemical deficits, including sulfatase activity and glycosaminoglycan accumulation, in affected organs of MSD mice treated post-symptom onset. In addition, treated mice demonstrated improved neuroinflammation and neurocognitive function. Together, these findings suggest that SUMF1 HSCT-GT can improve both biochemical and functional disease markers in the MSD mouse.
Presa M, Pham V, Ray S, Piec PA, Ryan J, Billings T, Coombs H, Schlotawa L, Lund T, Ahrens-Nicklas RC, Lutz C. Bone marrow transplantation increases sulfatase activity in somatic tissues in a multiple sulfatase deficiency mouse model. Commun Med (Lond). 2024 Oct 25;4(1):215. doi: 10.1038/s43856-024-00648-y. PMID: 39448727; PMCID: PMC11502872.
Abstract
Background: Multiple Sulfatase Deficiency (MSD) is an ultra-rare autosomal recessive disorder characterized by deficient enzymatic activity of all known sulfatases. MSD patients frequently carry two loss of function mutations in the SUMF1 gene, encoding a formylglycine-generating enzyme (FGE) that activates 17 different sulfatases. MSD patients show common features of other lysosomal diseases like mucopolysaccharidosis and metachromatic leukodystrophy, including neurologic impairments, developmental delay, and visceromegaly. There are currently no approved therapies for MSD patients. Hematopoietic stem cell transplant (HSCT) has been applied with success in the treatment of certain lysosomal diseases. In HSCT, donor-derived myeloid cells are a continuous source of active sulfatase enzymes that can be taken up by sulfatase-deficient host cells. Thus, HSCT could be a potential approach for the treatment of MSD.
Methods: To test this hypothesis, we used a clinically relevant mouse model for MSD, B6-Sumf1(S153P/S153P) mice, engrafted with bone marrow cells, Sumf1+/+, from B6-PtprcK302E mice (CD45.1 immunoreactive).
Results: After 10 months post-transplant, flow cytometric analysis shows an average of 90% of circulating leukocytes of donor origin (Sumf1(+/+)). Enzymatic activity for ARSA, ARSB, and SGSH is significantly increased in spleen of B6-Sumf1(S153P/S153P) recipient mice. In non-lymphoid organs, only liver and heart show a significant correction of sulfatase activity and GAG accumulation. Frequency of inflammatory cells and lysosomal pathology is significantly reduced in liver and heart, while no significant improvement is detected in brain.
Conclusions: Our results indicate that HSCT could be a suitable approach to treat MSD-pathology affecting peripheral organs, however that benefit to CNS pathology might be limited.
Plain language summary
Multiple Sulfatase Deficiency (MSD) is a rare genetic disorder caused by loss-of-function variations in the SUMF1 gene. This deficiency results in the accumulation of toxic compounds, leading to developmental delays and neurological impairments. In a bone marrow transplant (BMT), donor cells are infused into the patient and secrete active proteins that can help remove those toxic compounds. We carried out BMT in a mouse model for MSD and saw beneficial effects on peripheral organs, such as the liver and heart, but less change in neurological symptoms. Our results will be useful for the design of potential cell therapy approaches that could be used clinically to treat MSD.
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