HSPC transplant eases disease symptoms in Sanfilippo C mice
Motor function, kidney issues among symptoms resolved with transplant
A hematopoietic stem and progenitor cell (HSPC) transplant eased several disease symptoms, including motor problems and enlarged organs, in a new mouse model of Sanfilippo syndrome type C, according to a study.
HSPC transplant provides blood cell precursors from a healthy donor, which are then able to develop into mature cells capable of producing the enzyme that’s normally lacking in Sanfilippo type C, also known as mucopolysaccharidosis type IIIC (MPS IIIC).
“These data support that HSPC transplantation presents a promising therapeutic avenue for MPS IIIC and represents the first step toward the clinical translation of an HSPC-mediated therapy strategy,” the researchers wrote.
The study, “Transplantation of Wild-Type Hematopoietic Stem and Progenitor Cells Improves Disease Phenotypes in a Mucopolysaccharidosis IIIC Mouse Model,” was published in Cell Transplantation.
Sanfilippo syndrome is a rare, neurodegenerative disease affecting children, in which the complex sugar molecule heparan sulfate accumulates to toxic levels in cells due to genetic mutations that disrupt production of the enzymes needed to break it down. Each Sanfilippo disease type affects a different enzyme involved in the process. Sanfilippo type C is caused by mutations in the HGSNAT gene, leading to a deficiency in an enzyme of the same name.
Precursor cells give rise to healthy cells after transplant
Heparan sulfate accumulation drives a range of Sanfilippo symptoms, including developmental delays, behavioral problems, mobility loss, seizures, enlarged organs, and gastrointestinal or bladder issues.
HSPCs are precursor cells that give rise to mature blood cells, including red blood cells and white blood cells (immune cells).
The idea behind an HSPC transplant for Sanfilippo is to infuse HSPCs from a healthy donor into a patient, where they’ll then give rise to healthy cells capable of producing HGSNAT or other missing enzymes in various tissues, thereby easing disease symptoms.
A previous study found that HSPC transplant effectively eased neuroinflammation and corrected behavioral deficits in a mouse model of Sanfilippo type C, and had other benefits as well.
In the recent study, scientists further explored the potential benefits of HSPC transplant in a newly developed mouse model of the disease.
The mice showed characteristic features of Sanfilippo type C, including enlarged organs and neurological deficits. They also exhibited accumulation of glycosaminoglycans (GAGs) — the family of sugar molecules to which heparan sulfate belongs — and related molecules.
After the mice were transplanted with HSPCs from healthy mice, many of these disease features were at least partially reversed.
HGSNAT enzyme activity was increased, to levels that were 17% of normal in the brain, 3% of normal in the kidney, and 27% in the spleen, where most HSPC cells were successfully transplanted.
This was accompanied by reductions in heparan sulfate and other related disease-specific molecules.
Mice given the transplant exhibited improvements in motor function, reductions in spleen and bladder size, and an easing of urinary retention, a condition in which the bladder can’t be completely emptied during urination. Evidence of disease-related changes in the kidneys were also reduced.
Throughout the body, the transplanted cells appeared to develop into macrophages, a type of immune cell responsible for engulfing and clearing away waste products and harmful substances. Signs of inflammation in various tissues were reduced.
In the brain, the cells took on the characteristics of microglia, which are essentially brain- and spinal cord-resident macrophages. There, signs of inflammation and neuronal damage were reduced.
“Our data on the impact of … HSPCs in MPS IIIC are promising as they lead to the improvement of several complications,” the researchers wrote.
For Sanfilippo type A, scientists have developed a combined HSPC gene therapy approach to further boost the therapeutic benefits. With that approach, a person’s own HSPCs are collected and genetically modified to increase production of the missing enzyme before being transplanted back.
The researchers believe such an approach might also be of benefit for Sanfilippo type C.
They said the study’s findings represent “the first step toward a clinical translation of an HSPC gene therapy strategy for MPS IIIC.”
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