An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model

Abstract

Hematopoietic stem and progenitor cells (HSPCs) can lead to the establishment of a long-lasting microglia-like progeny in the brain of properly myeloablated hosts. We exploited this approach to treat the severe CLN1 neurodegenerative disorder, which is the most aggressive form of neuronal ceroid lipofuscinoses, due to deficiency of palmitoyl-protein thioesterase 1 (hPPT1). We here provide first evidence that: i) transplantation of wild type HSPCs exerts a partial but long-lasting mitigation of the symptoms; ii) transplantation of HSPCs over-expressing hPPT1 by lentiviral gene transfer enhances therapeutic benefit as compared to wild type cell transplant, with first demonstration of such a dose-effect benefit for a purely neurodegenerative condition like CLN1 disease; iii) transplantation of hPPT1 over-expressing HSPCs by a novel intracerebroventricular (ICV) approach is sufficient to transiently ameliorate CLN1 disease symptomatology in the absence of hematopoietic tissue engraftment of the transduced cells; and iv) the combinatorial transplantation of transduced HSPCs intravenously and ICV results in the most robust therapeutic benefit among the tested approaches on both pre-symptomatic as well as symptomatic animals. Overall, these findings provide first evidence of the efficacy and feasibility of this novel approach to treat CLN1 disease and possibly other neurodegenerative conditions, paving the way for its future clinical application.