Clinical Trial: Gene Therapy for Metachromatic Leukodystrophy
Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional
Official Title: A Phase I/II Clinical Trial of Hematopoietic Stem Cell Gene Therapy for the Treatment of Metachromatic Leukodystrophy
Brief Summary: This is a phase I/II protocol aiming at the assessment of the safety and efficacy of ARSA gene transfer into hematopoietic stem/progenitor cells for the treatment of Metachromatic Leukodystrophy.
Detailed Summary:
Metachromatic Leukodystrophy (MLD) is an autosomal recessive Lysosomal Storage Disorder (LSD) characterized by severe and progressive dysmyelination affecting the central and peripheral nervous system.
Hematopoietic cell transplantation (HCT) is ineffective in ameliorating patients' phenotype or delaying disease evolution. No evidences of efficacy of enzyme replacement strategies are available at the moment. Transplantation of genetically corrected autologous hematopoietic stem cells (HSC) could represent a novel and potentially efficacious treatment for MLD patients.
We are conducting a gene therapy clinical trial based on autologous HSC and advanced generation lentiviral vectors (LV) for patients affected by the most severe, early onset forms of the disease, based on our preclinical efficacy and safety data and on the experience we acquired from the treatment of Adenosine deaminase deficiency (ADA-SCID) patients by a similar approach. Our general goal is to demonstrate safety and efficacy of this gene therapy approach in MLD patients. We have developed and tested a clinically applicable LV containing the ARSA cDNA controlled by a constitutive eukaryotic promoter sequence. Preclinical studies aimed at assessing efficacy and safety of ARSA gene transfer using the selected vector have been conducted in the murine model of the disease and in progenitors and mature hematopoietic cells from MLD patients. The following results were obtained:
- efficient ARSA gene transfer;
- long term in vitro and in vivo multilineage ARSA expression;
- ability to prevent and correct neurological disease manifestations;
- good tolerance and long-term safety of the trea
Sponsor: GlaxoSmithKline
Current Primary Outcome:
- Conditioning regimen-related safety [ Time Frame: at +60 days after transplantation ]The absence of engraftment failure or delayed hematopoietic reconstitution (prolonged
- Conditioning regimen-related toxicity [ Time Frame: 3 years ]The absence of regimen related toxicity, as determined by a surveillance of clinical (NCI >2
- The short-term safety and tolerability of lentiviral-transduced cell infusion [ Time Frame: 48 hours after transplant ]It will be evaluated on the basis of adverse events reporting and monitoring of the systemic
- Improvement of GMFM score [ Time Frame: 24 months after treatment ]An improvement of 10% of the total GMFM score in treated patients, when compared to the
- Increase of residual ARSA activity [ Time Frame: 24 months after treatment ]A significant (≥ 2 SD) increase of residual ARSA activity as compared to pretreatment
- The long-term safety of lentiviral-transduced cell infusion [ Time Frame: 24 months after the treatment ]Absence of Replication Competent Lentivirus (RCL): ELISA for HIV p24 antigen
Original Primary Outcome:
- Conditioning regimen-related safety [ Time Frame: at +60 days after transplantation ]The absence of engraftment failure or delayed hematopoietic reconstitution (prolonged aplasia), defined as Absolute Neutrophil Count (ANC)<500/μl with no evidence of BM recovery, requiring cellular back-up administration.
- Conditioning regimen-related toxicity [ Time Frame: 3 years ]The absence of regimen related toxicity, as determined by a surveillance of clinical (NCI >2) and laboratory (NCI >3) parameters.
- The short-term safety and tolerability of lentiviral-transduced cell infusion [ Time Frame: 48 hours after transplant ]It will be evaluated on the basis of adverse events reporting and monitoring of the systemic reactions to cell infusion (fever, tachycardia, nausea and vomiting, joint pain, skin rash).
- Improvement of GMFM score [ Time Frame: 24 months after treatment ]An improvement of 10% of the total GMFM score in treated patients, when compared to the GMFM scores in control MLD population. GMFM is a clinically relevant endpoint being a direct measure of motor impairment and there is a causal relationship between the potential beneficial outcome measured with the GMFM and the treatment, being motor impairment consequent to the involvement of both CNS and PNS, and less influenced by other variables. A 10% modification of the total GMFM score is as a clinically relevant change according to the experience of therapists in children with cerebral palsy.
- Increase of residual ARSA ac
Current Secondary Outcome:
- The absence of immune responses against the transgene [ Time Frame: every three months for the first year, then once a year. ]Even if we do not expect immune responses against the functional ARSA enzyme,
- Improvement in the NCV Index for ENG and in the total score for MR [ Time Frame: 24 months after treatment ]An improvement in the NCV Index for ENG and in the total score for MR of ≥ 2 SD, when
- Transduced cell engraftment [ Time Frame: 12 months after treatment ]Transduced cell engraftment above 4% in PBMCs and CD34+ progenitors in BM
- IQ measurement above 55 [ Time Frame: 24, 30 and 36 months after treatment ]The measurement of an IQ above 55 (threshold for severe disability) at neuro-psychological
Original Secondary Outcome:
- The absence of immune responses against the transgene [ Time Frame: every three months for the first year, then once a year. ]Even if we do not expect immune responses against the functional ARSA enzyme, according to our preclinical data and having most of MLD patients residual enzymatic activity, treated patients will be monitored for antibodies anti-ARSA (immunoblot analyses).
- Improvement in the NCV Index for ENG and in the total score for MR [ Time Frame: 24 months after treatment. ]An improvement in the NCV Index for ENG and in the total score for MR of ≥ 2 SD, when compared to the scores observed in the historical control MLD population. ENG and MR were validated as informative quantitative instrumental read outs during our natural history study.
- Transduced cell engraftment [ Time Frame: 12 months after treatment ]Transduced cell engraftment above 4% in PBMCs and CD34+ progenitors in BM (determined as VCN/cell ≥0.04 at quantitative PCR, equivalent to 4% assuming a VCN of 1). This value is based on clinical experience in other gene therapy trials, which has demonstrated 4% average long-term engraftment of autologous hematopoietic stem/progenitor cells transduced with onco-retroviral vectors in the bone marrow of pediatric patients suffering from immunodeficiency (ADA-SCID) and receiving reduced intensity, non-myeloablative conditioning.
Information By: GlaxoSmithKline
Dates:
Date Received: March 16, 2012
Date Started: May 2010
Date Completion: April 2023
Last Updated: March 22, 2017
Last Verified: March 2017
- The absence of immune responses against the transgene [ Time Frame: every three months for the first year, then once a year. ]
- Conditioning regimen-related safety [ Time Frame: at +60 days after transplantation ]
