Gene Therapy in Patients With Mucopolysaccharidosis Disease

NCT03173521 | Completed Phase 1

• 1 other identifier: TIGEM1-MPS VI
• Study Type: interventional
• Target: 9
• Locations: 2 countries
• Sites: 2

Brief Summary

This study investigated the safety and efficacy of gene therapy approaches for Mucopolysaccharidosis type VI disease caused by the deficiency of arylsulfatase B (ARSB) enzyme. The aim of the study is to evaluate the safety and efficacy of the treatment.

Conditions

Mucopolysaccharidosis Type VI

Keywords

MPSVI

Outcome Measures

Primary Outcomes (2)

• Safety and tolerability of the IMP administration

  Overall safety and tolerability will be determined through monitoring of adverse events, laboratory and clinical investigations and imaging studies (for example complete physical examination with vital signs recording, liver ultrasound, measurement of transaminases, thyroids hormones, creatinine, albumin, total proteins in blood and urine, and urea, C3 and C4 in blood).

  From GT up to 5 years post IMP administration at the following visits: days 1,2,3; weeks 2,3,6,7,8,9,10,11,12,13,14; months 4,9,12; years 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5.

• Primary efficacy outcome - Urinary GAG levels

  To determine the efficacy of gene therapy, post-injection urinary GAG excretion levels will be compared to the average of pre-injection urinary GAG determined at baseline 1 and at visit 1.

  From GT up to 5 years post IMP administration at the following visits: days 1,2,3; months 4,9,12,15; years 1.5,1.75, 2, 2.5, 3, 4, 5.

Secondary Outcomes (2)

• Secondary efficacy outcome - endurance

  From GT up to 5 years post IMP administration at the following visits: months 4,9,12; years 1.5, 2, 2.5, 3.

• Secondary efficacy outcome - lung volumes

  From GT up to 5 years post IMP administration at the following visits: months 4,9,12; years 1.5, 2, 2.5, 3.

Study Arms (1)

open label

EXPERIMENTAL

Adeno-associated viral vector serotype 8 with liver-specific thyroxine-binding globulin (TBG) promoter driving the expression of the human ARSB gene diluted in its final formulation medium \[Drug product (DP) diluted in 0.9% saline solution and 0.25% of human serum albumin\]. Four dose levels are available: * 'Starting dose' is 6x1011 gc of vector per kg of body weight. * 'High dose' is 2x1012 gc of vector per kg of body weight. * 'Very high dose' is 6x1012 gc of vector per kg of body weight. * 'Low dose' is 2x1011 gc of vector per kg of body weight. Intermediate doses are also possible. The administration of the IMP will be performed into a peripheral vein (e.g. median cubital vein) over 2-4 hours using an infusion pump. The IMP final volume to be injected is calculated based on the patient's weight (determined on the day of hospital admission), as 3 mL/kg.

Biological: AAV2/8.TBG.hARSB

Interventions

AAV2/8.TBG.hARSB BIOLOGICAL

Adeno-associated viral vector serotype 8 with liver-specific thyroxinebinding globulin (TBG) promoter driving the expression of the human ARSB gene. Four dose levels are available: * Starting dose is 6x1011 gc of vector per kg of body weight; * High dose is 2x1012 gc of vector per kg of body weight and will be administered after at least two subjects at the starting dose have experienced no DLT; * Very high dose is 6x1012 vector per kg of body weight and will be administered after three subjects at the high dose have experienced no DLT; * Low dose is 2x1011 gc of vector per kg of body weight. Intermediate doses are also possible. The administration of the IMP will be performed into a peripheral vein. The IMP final volume to be injected is calculated based on the patient's weight (determined on the day of hospital admission), as 3 mL/kg.

open label

Eligibility Criteria

• Age: 4 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Documented biochemical and molecular diagnosis of MPS VI. Testing for homozygous or compound heterozygous disease-causing mutations of the ARSB gene must have been performed by an accredited laboratory.
• Subjects must be of 4 years of age or older.
• Subjects should have received ERT for at least 12 months before enrolment and should continue to receive ERT until 7-14 days before IMP administration.
• Documented informed consent; willingness to adhere to protocol and to participate to long-term follow-up, as evidenced by written informed consent.

You may not qualify if:

• Subjects unable or unwilling to meet requirements of the study.
• Participation in a clinical study with an investigational drug in the 6 months prior to enrolment in this trial.
• Subjects unable to perform the 6MWT.
• History of severe anaphylactoid reaction to Naglazyme in subjects receiving ERT that could affect the safety (severe reaction is meant to be a respiratory impairment event that is life-threatening).
• Presence of tracheostomy or need of ventilatory assistance.
• Subjects with evidence of progressive myelomalacia that is considered severe enough to require neck surgery in the first six months after enrolment.
• Values of AST or ALT above the upper limit of normal range at baseline 2 (at -5days) evaluations.
• Co-existence of chronic diseases or clinically relevant abnormal baseline laboratory values; infections with hepatitis B, C, or HIV (Baseline 1).
• Systemic corticosteroid therapy or other immunosuppressive/immunomodulating drugs within 2 months prior to IMP administration.
• Female individuals of childbearing age who are pregnant or nursing or unwilling to use effective contraception for at least one year post-IMP administration.
• Fertile male individuals who are unwilling to use male barrier contraceptives such as condom.
• Any other condition that would not allow the subject to complete follow-up examinations during the course of the study and that, in the opinion of the Investigator, would make the subject unsuitable for the study.
• Presence of serum NAB to AAV8 above the limit of detection of the assay (Screening and Baseline 1).
• Presence of serum antibodies anti-ARSB above the upper limit of detection of the assay (antibodies anti-ARSB level \>31250 or declared positive at the value of serum dilution 1.10 according to the performed assay) at Screening and Baseline 1.

Sponsors & Collaborators

• Fondazione Telethon: lead

Study Sites (2)

Department of Translational Medicine (DISMET) of "Federico II" University, Naples

Naples, 80131, Italy

Location

Children's Hospital Hacettepe University

Ankara, Turkey (Türkiye)

Location

Related Publications (2)

• Rossi A, Romano R, Fecarotta S, Dell'Anno M, Pecorella V, Passeggio R, Zancan S, Parenti G, Santamaria F, Borgia F, Deodato F, Funghini S, Rupar CA, Prasad C, O'Callaghan M, Mitchell JJ, Valsecchi MG, la Marca G, Galimberti S, Auricchio A, Brunetti-Pierri N. Multi-year enzyme expression in patients with mucopolysaccharidosis type VI after liver-directed gene therapy. Med. 2025 Apr 11;6(4):100544. doi: 10.1016/j.medj.2024.10.021. Epub 2024 Nov 14.

  PMID: 39547230 DERIVED

• Brunetti-Pierri N, Ferla R, Ginocchio VM, Rossi A, Fecarotta S, Romano R, Parenti G, Yildiz Y, Zancan S, Pecorella V, Dell'Anno M, Graziano M, Alliegro M, Andria G, Santamaria F, Brunetti-Pierri R, Simonelli F, Nigro V, Vargas M, Servillo G, Borgia F, Soscia E, Gargaro M, Funghini S, Tedesco N, Le Brun PR, Rupar CA, Prasad C, O'Callaghan M, Mitchell JJ, Danos O, Marteau JB, Galimberti S, Valsecchi MG, Veron P, Mingozzi F, Fallarino F, la Marca G, Sivri HS, Auricchio A. Liver-Directed Adeno-Associated Virus-Mediated Gene Therapy for Mucopolysaccharidosis Type VI. NEJM Evid. 2022 Jul;1(7):EVIDoa2200052. doi: 10.1056/EVIDoa2200052. Epub 2022 Jun 6.

  PMID: 38319253 DERIVED

MeSH Terms

Conditions

Mucopolysaccharidosis VI

Condition Hierarchy (Ancestors)

Mucopolysaccharidoses; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Nicola Brunetti-Pierri

  Department of Translational Medicine (DISMET) of "Federico II" University, Naples

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Open Label

Study Record Dates

• First Submitted: April 12, 2017
• First Posted: June 2, 2017
• Study Start: July 17, 2017
• Primary Completion: July 30, 2021
• Study Completion: July 16, 2024
• Last Updated: November 22, 2024

Record last verified: 2024-11

Locations

IT (1); TU (1)