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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.

SUBMITTER: Peviani M

PROVIDER: S-EPMC10086581 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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

Peviani Marco M Das Sabyasachi S Patel Janki J Jno-Charles Odella O Kumar Rajesh R Zguro Ana A Mathews Tyler D TD Cabras Paolo P Milazzo Rita R Cavalca Eleonora E Poletti Valentina V Biffi Alessandra A

EMBO molecular medicine 20230306 4

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 s ...[more]

PMID: 36876653

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Project description:BackgroundIn X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation.MethodsWe enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2-3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion.ResultsA total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications.ConclusionsEarly results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102 ; ClinicalTrialsRegister.eu number, 2011-001953-10 .).

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

Publications

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

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