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

Abstract

Hematopoietic stem and progenitor cells (HSPCs) can establish a long‐lasting microglia‐like progeny in the central nervous system 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 palmitoyl‐protein thioesterase‐1 (PPT1) deficiency. We here provide the first evidence that (i) transplantation of wild‐type HSPCs exerts partial but long‐lasting mitigation of CLN1 symptoms; (ii) transplantation of HSPCs over‐expressing hPPT1 by lentiviral gene transfer enhances the therapeutic benefit of HSPCs 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‐symptoms in the absence of hematopoietic tissue engraftment of the transduced cells; and (iv) combinatorial transplantation of transduced HSPCs intravenously and ICV results in a robust therapeutic benefit, particularly on symptomatic animals. Overall, these findings provide first evidence of efficacy and feasibility of this novel approach to treat CLN1 disease and possibly other neurodegenerative conditions, paving the way for its future clinical application.

Targeted gene addition at the CX3CR1 locus of human HSPCs improves their ability to repopulate the myeloid CNS compartment and drives lineage specific and robust transgene expression in their CNS progeny

“…At sacrifice, 45 days later, a high and comparable engraftment of the donor cells was observed in hematopoietic organs (IV administration) and brain (IV and ICV administration) of transplant recipients in all the experimental groups (Supplementary Fig. 1D, E); no donor cells were observed in the hematopoietic organs of mice transplanted ICV (data not shown), in line with previous data 20,21 .…”

Prostaglandin E2 as transduction enhancer affects competitive engraftment of human hematopoietic stem and progenitor cells

“…Human CD34 + cells derived from granulocyte colony-stimulating factor (G-CSF) mPB of healthy donors were mock transduced or transduced with a LV designed for the GT of neuronal ceroid lipofuscinosis (LV.PPT1co) 20 in STD 17 or with the addition of PGE2 to the standard transduction cocktail, used with a timing and concentration previously demonstrated to enhance LV transduction (10 μM, added two hours before transduction). 8 To further test the effect of PGE2 on cell culture and transduction, we also anticipated its use to the time of thawing.…”

Recent insights into the networking of CLN genes and proteins in mammalian cells

“…For example, Brineura is an approved enzyme replacement therapy for CLN2 disease (Lewis et al, 2020). In addition, gene therapy is currently being explored as a treatment option for several subtypes of NCL (Cain et al, 2019;Chen et al, 2022;Johnson et al, 2021;Kick et al, 2023;Kleine Holthaus et al, 2019, 2020Murray et al, 2021;Peviani et al, 2023;White et al, 2021).…”

“…For example, Brineura is an approved enzyme replacement therapy for CLN2 disease (Lewis et al, 2020). In addition, gene therapy is currently being explored as a treatment option for several subtypes of NCL (Cain et al, 2019; Chen et al, 2022; Johnson et al, 2021; Kick et al, 2023; Kleine Holthaus et al, 2019, 2020; Murray et al, 2021; Peviani et al, 2023; White et al, 2021). Furthermore, efforts are being made to explore the repurposing of drugs for NCL and identifying biomarkers for monitoring disease progression and the patient response to therapy (Huber, 2021; Soldati et al, 2021).…”