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  • Periodic Report Summary 2 - HSCSFORLSDBRAIN (HSC-based therapies for LSDs: understanding the modalities of cell replacement in the LSD brain for improving therapeutic efficacy)
ERC

HSCSFORLSDBRAIN Report Summary

Project ID: 617162
Funded under: FP7-IDEAS-ERC
Country: Italy

Periodic Report Summary 2 - HSCSFORLSDBRAIN (HSC-based therapies for LSDs: understanding the modalities of cell replacement in the LSD brain for improving therapeutic efficacy)

The recent hypothesis that postnatal microglia are maintained independently of circulating monocytes by local precursors that colonize the brain before birth has relevant implications for the treatment of various neurological diseases, including lysosomal storage disorders (LSDs). LSDs are fatal diseases of childhood occurring in 1:5000-7000 live births; in >50% of the cases, LSD patients experience a severe neurological deterioration. Most LSDs with central nervous system (CNS) involvement lack a curative treatment. Hematopoietic cell transplantation (HCT) form healthy donors is applied to LSD patients to repopulate the recipient myeloid compartment, including CNS microglia, with donor-derived cells expressing the defective functional hydrolase. Over the past three decades, about 1000 HCTs have been performed for patients with LSDs with a variable benefit exerted on the CNS with a variable, but overall modest outcome. Indeed, timing of resident CNS macrophages and microglia replacement by the transplanted cell progeny is frequently too slow for clinical benefit due to the rapid progression of the primary neurological disease, particularly in the most aggressive LSD variants. Thus, goal of the project is to combine basic and innovative preclinical research with the information derived from a pioneering clinical experience to generate the basis for designing more efficacious and safer transplant approaches for these fatal diseases. The new knowledge generated by the project thus far has resulted in the availability of a highly innovative platform technology for the efficient and timely generation of engineered microglia-like cells in the brain (exclusively or in association to the generation of engineered blood cells in the circulation and within tissues). The engineered cells could exert therapeutic effects in a variety of neurodegenerative conditions characterized by neuroinflammation, oxidative stress and neural loss by releasing defective proteins (i.e. lysosomal enzymes), trophic or neurotrophic factors or other therapeutically relevant molecules. This is therefore novel knowledge with high interdisciplinary and translational value that will be further developed and exploited in the second part of the project to treat two prototypical LSDs with severe brain involvement in the animal models.

Reported by

Ospedale San Raffaele
Italy
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