HSC Gene Therapy for LSDs: Understanding the Modalities of Cell Replacement in the LSD Brain for Improving Therapeutic Efficacy

From the impressive results originally obtained in Hurler syndrome, it was expected that Hematopoietic Cell Transplantation (HCT-transplantation of blood forming cells) could alleviate most Lysosomal Storage Disorders (LSDs). However, HCT was proven to provide diverse degree of benefit according to the disease, the involvement of the central nervous system and its stage at time of transplant and, in particular, it was proved to be ineffective in LSD patients with overt neurological symptoms or in those with early onset or aggressive infantile forms. In the previous funding period, we have addressed this issue of limited HCT efficacy by increasing by gene therapy the capability of the transplanted cell progeny to deliver the therapeutic enzyme to the affected tissues. Based on the promising results obtained with this approach, a clinical trial of hematopoietic stem cell gene therapy is currently active in Metachromatic Leukodystrophy, while clinical development plans are in place for Mucopolysaccharidosis type I and Globoid Cell Leukodystrophy. However, enhancing infiltration of the donor cells into the affected central nervous system after HCT would also be of great relevance for anticipating the time of clinical benefit and improving the efficacy of the transplant procedure. The current funding proposal is based on recent relevant results obtained by us on this aspect and is aimed at studying more in depth the modalities of brain infiltration by gene corrected cells after HCT, with the final goal of improving current transplant protocols. Moreover, our recent work has prompted the development of a novel and less invasive approach for treating LSDs having a prevalent or exclusive central nervous system involvement, sparing the hematopoietic system or other peripheral organs from toxicity; this approach will be developed in the context of relevant LSD models.