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Cellular and Biochemical Underpinnings of Stem Cell Gene Therapies for Cystinosis


Cystinosis is an early onset multisystemic lysosomal storage disorder characterized by deleterious CTNS gene mutations causing defective export and crystallization of amino acid dimer cysteine within lysosomes. Previous studies found that wild-type hematopoietic stem and progenitor cell (HSPC) transplantation into cystinotic (Ctns-/-) mice prevents disease progression via HSPC-derived macrophage-mediated TNT delivery of functional Ctns-carrying lysosomes to diseased cells. While Phase I/II clinical trials for ex vivo lentivirally gene-corrected autologous HSPC transplantation is ongoing at UC San Diego, this approach does not yet extend to 40% of patients harboring homozygous 57 kilobase pair mutations eliminating both CTNS and neighboring pentose phosphate pathway SHPK genes. With roles in both metabolism and macrophage polarization, understanding the clinical relevance of SHPK to our macrophage-based gene therapy is essential to elucidate if SHPK-deficient patients are likely to benefit from the therapy. In this pursuit, we examined the role of polarization conditions mediating macrophage-derived TNT intracellular trafficking in robust in vitro and in vivo systems. We generated novel Shpk knockout (Shpk-/-) mice models which upheld mild metabolic phenotypes as a consequence of isolated Shpk-deficiency. Furthermore, we found that Shpk-/-/Ctns+/+ HSPC transplantation into lethally-irradiated cystinotic Ctns-/-/Shpk+/+ mice resulted in normal macrophage tissue integration, restored Ctns mRNA expression, reduced cystine content, and improved renal function, inducing widespread disease rescue. Ultimately, these findings provide insight into the pathogenic role of SHPK in cystinosis, validate the utility of HSPC transplantations as gene-modifying therapies for disorders of similar cellular/molecular underpinnings, and confirms eligibility of patients with SHPK-deficiency for cystinosis clinical trials.

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