Gene Therapy for Metachromatic Leukodystrophy (MLD)

Conditions

Lysosomal Storage Disease, Metachromatic Leukodystrophy

Keywords

OTL-200, Metachromatic Leukodystrophy, Gene Therapy, MLD, Previously GSK2696274

Brief summary

This Phase I/II clinical trial consists of the application of lentiviral vector-based gene therapy to patients affected by Metachromatic Leukodystrophy (MLD), a rare inherited Lysosomal Storage Disorder (LSD) resulting from mutations in the gene encoding the Arylsulfatase A (ARSA) enzyme. The medicinal product consists of autologous CD34+ hematopoietic stem/progenitor cells in which a functional ARSA cDNA is introduced by means of 3rd generation VSV-G pseudotyped lentiviral vectors.

Francesca Fumagalli, Valeria Calbi, Vera Gallo, Alberto A. Zambon, Salvatore Recupero et al. (51 authors)

New England Journal of Medicine2025-04-2312 citations

10.1056/nejmoa2405727

Monitoramento do Horizonte Tecnológico como ferramenta de sustentabilidade: atidarsagene autotemcel

Monica Souza, Antônia I. S. Ximenes, Kátia Elizabete Galdino, Ketinlly Yasmyne Nascimento Martins, C. Prado et al. (7 authors)

Jornal de Assistência Farmacêutica e Farmacoeconomia2024-11-30

10.22563/2525-7323.2024.v9.s1.p.192

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.

Fumagalli F, Calbi V, Natali Sora MG, Sessa M, Baldoli C, Rancoita PMV, Ciotti F, Sarzana M, Fraschini M, Zambon AA, Acquati S, Redaelli D, Attanasio V, Miglietta S, De Mattia F, Barzaghi F, Ferrua F, Migliavacca M, Tucci F, Gallo V, Del Carro U, Canale S, Spiga I, Lorioli L, Recupero S, Fratini ES, Morena F, Silvani P, Calvi MR, Facchini M, Locatelli S, Corti A, Zancan S, Antonioli G, Farinelli G, Gabaldo M, Garcia-Segovia J, Schwab LC, Downey GF, Filippi M, Cicalese MP, Martino S, Di Serio C, Ciceri F, Bernardo ME, Naldini L, Biffi A, Aiuti A.

2022-01-01191 citations

10.1016/s0140-6736(21)02017-1

Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial.

Sessa M, Lorioli L, Fumagalli F, Acquati S, Redaelli D, Baldoli C, Canale S, Lopez ID, Morena F, Calabria A, Fiori R, Silvani P, Rancoita PM, Gabaldo M, Benedicenti F, Antonioli G, Assanelli A, Cicalese MP, Del Carro U, Sora MG, Martino S, Quattrini A, Montini E, Di Serio C, Ciceri F, Roncarolo MG, Aiuti A, Naldini L, Biffi A.

2016-06-08377 citations

10.1016/s0140-6736(16)30374-9

Interventions

GENETICOTL-200 Gene Therapy

Autologous hematopoietic stem/progenitor cells collected from the bone marrow and transduced ex vivo with a Lentiviral vector encoding the human ARSA cDNA

Study design

Allocation

NA

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

No minimum to 7 Years

Healthy volunteers

No

Inclusion criteria

* Pre-symptomatic MLD patients with the late infantile variant; * Pre- or early-symptomatic MLD patients with the early juvenile variant; * Patients for whom parental/guardian signed informed consent has been obtained.

Exclusion criteria

* HIV RNA and/or HCV RNA and/or HBV DNA positive patients; * Patients affected by neoplastic diseases; * Patients with cytogenetic alterations typical of MDS/AML; * Patients with end-organ functions or any other severe disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study; * Patients enrolled in other trials/other therapeutic approaches that might become available; * Patient who underwent allogeneic hematopoietic stem cell transplantation in the previous six months; * Patient who underwent allogenic hematopoietic stem cell transplantation with evidence of residual cells of donor origin.

Design outcomes

Primary

Measure	Time frame	Description
Improvement of Gross Motor Function Measure (GMFM) score	24 months after treatment	An improvement of 10% of the total GMFM score in treated patients, when compared to the GMFM scores in the historical control MLD population, evaluated 24 months after treatment.
Increase of residual Arylsulfatase A (ARSA) activity	24 months after treatment	A significant increase of residual ARSA activity as compared to pre- treatment values, measured in total Peripheral Blood Mononuclear Cells (PBMCs)
Conditioning regimen-related safety	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 Bone Marrow (BM) recovery, requiring cellular back-up administration.
Conditioning regimen-related toxicity	3 years after treatment	The absence of regimen related toxicity, as determined by a surveillance of adverse events (AEs) (NCI ≥2) and laboratory parameters (NCI ≥3) that will be applied in the short- and long-term follow-up of the treated patients in order to assess the degree of morbidity associated to the conditioning regimen
The short-term safety and tolerability of lentiviral-transduced cell infusion	48 hours after treatment infusion	It will be evaluated on the basis of AEs reporting and monitoring of the systemic reactions to cell infusion (fever, tachycardia, nausea and vomiting, joint pain, skin rash). Evaluation will also consist of the absence of Serious Adverse Reactions (SARs) within 48 hours after infusion.
The long-term safety of lentiviral-transduced cell infusion	baseline, 1, 3, 6, and 12 months after treatment, then once a year	Absence of Replication Competent Lentivirus: Assessed via enzyme-linked immunosorbent assay (ELISA) test for serum human immunodeficiency virus (HIV) p24 antigen. Positive HIV p24 test result is subject to second level testing including: a) DNA PCR for vesicular stomatitis virus G (VSV-G) envelope (PBMC) and b) reverse transcription (RT) PCR for HIV-pol ribonucleic acid (RNA) (plasma).

Secondary

Measure	Time frame	Description
The absence of immune responses against the transgene (immunoblot analyses).	baseline, 3, 6, and 12 months after treatment, then once a year	Even if immune responses against the functional ARSA enzyme are not expected, treated subjects will be monitored for anti-ARSA antibodies on a defined schedule.
Nerve Conduction Velocity (NCV) Index for Electroneurography (ENG) and total brain MRI score.	24 months after treatment	The NCV Index and the total brain MRI score will be compared to scores observed in the historical control MLD population. Gross Motor Function Classification for MLD (GMFC-MLD) levels at different ages compared to the historical control MLD population.
Transduced cell engraftment	12 months after treatment	Transduced cell engraftment above 4% in bone marrow-derived clonogenic progenitor cells, assessed as the percentage of LV-positive colonies. Vector copy number (VCN) per cell in total PBMC, total BM, and peripheral blood (PB) and bone marrow (BM) cell subpopulations will also be evaluated.
IQ measurement above 55	24, 30 and 36 months after treatment	The measurement of an IQ above 55 (threshold for severe cognitive impairment) at neuro-psychological testings

Countries

Italy

Outcome results

None listed