Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access

Abstract

Summary Background Effective treatment for metachromatic leukodystrophy (MLD) remains a substantial unmet medical need. In this study we investigated the safety and efficacy of atidarsagene autotemcel (arsa-cel) in patients with MLD. Methods This study is an integrated analysis of results from a prospective, non-randomised, phase 1/2 clinical study and expanded-access frameworks. 29 paediatric patients with pre-symptomatic or early-symptomatic early-onset MLD with biochemical and molecular confirmation of diagnosis were treated with arsa-cel, a gene therapy containing an autologous haematopoietic stem and progenitor cell (HSPC) population transduced ex vivo with a lentiviral vector encoding human arylsulfatase A (ARSA) cDNA, and compared with an untreated natural history (NHx) cohort of 31 patients with early-onset MLD, matched by age and disease subtype. Patients were treated and followed up at Ospedale San Raffaele, Milan, Italy. The coprimary efficacy endpoints were an improvement of more than 10% in total gross motor function measure score at 2 years after treatment in treated patients compared with controls, and change from baseline of total peripheral blood mononuclear cell (PBMC) ARSA activity at 2 years after treatment compared with values before treatment. This phase 1/2 study is registered with ClinicalTrials.gov , NCT01560182 . Findings At the time of analyses, 26 patients treated with arsa-cel were alive with median follow-up of 3·16 years (range 0·64–7·51). Two patients died due to disease progression and one due to a sudden event deemed unlikely to be related to treatment. After busulfan conditioning, all arsa-cel treated patients showed sustained multilineage engraftment of genetically modified HSPCs. ARSA activity in PBMCs was significantly increased above baseline 2 years after treatment by a mean 18·7-fold (95% CI 8·3–42·2; p<0·0001) in patients with the late-infantile variant and 5·7-fold (2·6–12·4; p<0·0001) in patients with the early-juvenile variant. Mean differences in total scores for gross motor function measure between treated patients and age-matched and disease subtype-matched NHx patients 2 years after treatment were significant for both patients with late-infantile MLD (66% [95% CI 48·9–82·3]) and early-juvenile MLD (42% [12·3–71·8]). Most treated patients progressively acquired motor skills within the predicted range of healthy children or had stabilised motor performance (maintaining the ability to walk). Further, most displayed normal cognitive development and prevention or delay of central and peripheral demyelination and brain atrophy throughout follow-up; treatment benefits were particularly apparent in patients treated before symptom onset. The infusion was well tolerated and there was no evidence of abnormal clonal proliferation or replication-competent lentivirus. All patients had at least one grade 3 or higher adverse event; most were...

Hematopoietic Stem Cell Transplantation for Neurological Disorders: A Focus on Inborn Errors of Metabolism

“…MLD was one of the first LSD in which the efficacy of gene therapy was demonstrated. Recently, Fumagalli et al (2022) published the long-term results of a phased 1/2 trial of lentiviral HSC-GT for patients with early-onset disease. Treatment was of meaningful clinical benefit, resulting in normal activity of the defective enzyme, which translated into prevention, stabilization, or reduced rate of neurological decline.…”

“…Treatment was of meaningful clinical benefit, resulting in normal activity of the defective enzyme, which translated into prevention, stabilization, or reduced rate of neurological decline. Of note, enzyme activity in the cerebrospinal fluid of treated patients was shown to be restored to normal levels, suggesting efficient brain engraftment of enhanced cells ( Fumagalli et al, 2022 ).…”

“…In this manner, autologous HSC are used as cellular vehicles of the missing enzyme to affected tissues such as the brain, enabling metabolic correction, clearance of storage materials, and ultimately repair. Currently, HSC-GT is emerging as an alternative to Allo-HSCT in the treatment of certain IEM such as X-linked Adrenoleukodystrophy, Hurler Syndrome, and Metachromatic Leukodystrophy ( Eichler et al, 2017 ; Gentner et al, 2021 ; Fumagalli et al, 2022 ).…”

Gene Therapy for Mitochondrial Diseases: Current Status and Future Perspective

“…In addition, part of the 5 -LTR, which contains the TATA box and transcription factor binding sites, can be partially deleted, creating a self-inactivating vector packaging system following integration into the host genome [35]. LVs are mainly used in ex vivo gene therapy, with successful application in the treatment of immune deficiencies [36] and leukodystrophies [37].…”

Advantages and Limitations of Gene Therapy and Gene Editing for Friedreich’s Ataxia

“…and, 6) HSPC-derived macrophages and microglia can deliver lacking protein/enzyme to the disease cells in the injured tissues ( Tan et al, 2019 ). Clinical trials using gene-modified autologous CD34 + HSPCs are being undertaken for genetic diseases such as X-SCID, ADA-SCID, Wiskott-Aldrich syndrome, metachromatic leukodystrophy, X-linked cerebral adrenoleukodystrophy, and mucopolysaccharidosis type I ( Gentner et al, 2021 ; Mamcarz et al, 2019 ; De Ravin et al, 2016 ; Kohn et al, 2021 ; Magnani et al, 2022 ; Ma et al, 2021 ; Ferrua and Aiuti, 2017 ; Morris et al, 2017 ; Biffi et al, 2013 ; Eichler et al, 2017b ; Fumagalli et al, 2022 ). Currently, our lab is conducting a phase 1/2 clinical trial for cystinosis ( ClinicalTrials.gov Identifier: NCT03897361), a multisystemic lysosomal storage disorder, characterized by accumulation of cystine in all tissues and due to mutations or deletions in CTNS gene, encoding a lysosomal cystine transporter ( Cherqui, 2021 ).…”