Gene Therapy in Patients With Mucopolysaccharidosis Disease

• Sponsor: Fondazione Telethon
• Information provided by (Responsible Party): Nicola Brunetti-Pierri, Fondazione Telethon

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Mucopolysaccharidosis Type VI	Biological: AAV2/8.TBG.hARSB	Phase 1; Phase 2

Detailed Description:

Mucopolysaccharidosis type VI disease is involved in Lysosomal Storage Disorder. The MPS VI disease is characterized by growth retardation, corneal clouding, cardiac valve disease, organomegaly, skeletal dysplasia, without central nervous system involvement.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 10 participants
• Intervention Model: Single Group Assignment
• Intervention Model Description: Open Label
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Open Label, Dose Escalation, Safety Study in Subjects With Mucopolysaccharidosis Type VI (MPS VI) Using Adeno-Associated Viral Vector 8 to Deliver the Human ARSB Gene to Liver
• Actual Study Start Date: July 17, 2017
• Estimated Primary Completion Date: April 30, 2020
• Estimated Study Completion Date: June 1, 2022

Arms and Interventions

Arm

Intervention/treatment

Experimental: open label

Biological: AAV2/8.TBG.hARSB; Adeno-associated viral vector serotype 8 with liver-specific thyroxinebinding globulin (TBG) promoter driving the expression of the human ARSB gene. Three 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; 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.

Outcome Measures

Primary Outcome Measures :

1. Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: from gene therapy until fourteen weeks ]
   Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
2. Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 4 months post gene therapy ]
   Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
3. Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 9 months post gene therapy ]
   Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
4. Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 12 months post gene therapy ]
   Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
5. Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 18 months post gene therapy ]
   Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
6. Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 24 months post gene therapy ]
   Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
7. Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 30 months post gene therapy ]
   Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
8. Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 36 months post gene therapy ]
   Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
9. efficacy urinary GAG [ Time Frame: 4 months post gene therapy ]
   ug GAG/mg creatinine
10. efficacy urinary GAG [ Time Frame: 9 months post gene therapy ]
    ug GAG/mg creatinine
11. efficacy urinary GAG [ Time Frame: 12 months post gene therapy ]
    ug GAG/mg creatinine
12. efficacy urinary GAG [ Time Frame: 18 months post gene therapy ]
    ug GAG/mg creatinine
13. efficacy urinary GAG [ Time Frame: 24 months post gene therapy ]
    ug GAG/mg creatinine
14. efficacy urinary GAG [ Time Frame: 30 months post gene therapy ]
    ug GAG/mg creatinine
15. efficacy urinary GAG [ Time Frame: 36 months post gene therapy ]
    ug GAG/mg creatinine

Secondary Outcome Measures :

1. efficacy Forced vital capacity [ Time Frame: 4 months post gene therapy ]
   percentage
2. efficacy Forced vital capacity [ Time Frame: 9 months post gene therapy ]
   percentage
3. efficacy Forced vital capacity [ Time Frame: 12 months post gene therapy ]
   percentage
4. efficacy Forced vital capacity [ Time Frame: 18 months post gene therapy ]
   percentage
5. efficacy Forced vital capacity [ Time Frame: 24 months post gene therapy ]
   percentage
6. efficacy Forced vital capacity [ Time Frame: 30 months post gene therapy ]
   percentage
7. efficacy Forced vital capacity [ Time Frame: 36 months post gene therapy ]
   percentage
8. efficacy forced expiratory volume at 1 second [ Time Frame: 4 months post gene therapy ]
   percentage
9. efficacy forced expiratory volume at 1 second [ Time Frame: 9 months post gene therapy ]
   percentage
10. efficacy forced expiratory volume at 1 second [ Time Frame: 12 months post gene therapy ]
    percentage
11. efficacy forced expiratory volume at 1 second [ Time Frame: 18 months post gene therapy ]
    percentage
12. efficacy forced expiratory volume at 1 second [ Time Frame: 24 months post gene therapy ]
    percentage
13. efficacy forced expiratory volume at 1 second [ Time Frame: 30 months post gene therapy ]
    percentage
14. efficacy forced expiratory volume at 1 second [ Time Frame: 36 months post gene therapy ]
    percentage
15. efficacy 6 minute walking test [ Time Frame: 4 months post gene therapy ]
    meter
16. efficacy 6 minute walking test [ Time Frame: 9 months post gene therapy ]
    meter
17. efficacy 6 minute walking test [ Time Frame: 12 months post gene therapy ]
    meter
18. efficacy 6 minute walking test [ Time Frame: 18 months post gene therapy ]
    meter
19. efficacy 6 minute walking test [ Time Frame: 24 months post gene therapy ]
    meter
20. efficacy 6 minute walking test [ Time Frame: 30 months post gene therapy ]
    meter
21. efficacy 6 minute walking test [ Time Frame: 36 monthspost gene therapy ]
    meter
22. efficacy 3 minute stair climb test [ Time Frame: 4 months post gene therapy ]
    number of stair climbed
23. efficacy 3 minute stair climb test [ Time Frame: 9 months post gene therapy ]
    number of stair climbed
24. efficacy 3 minute stair climb test [ Time Frame: 12 months post gene therapy ]
    number of stair climbed
25. efficacy 3 minute stair climb test [ Time Frame: 18 months post gene therapy ]
    number of stair climbed
26. efficacy 3 minute stair climb test [ Time Frame: 24 months post gene therapy ]
    number of stair climbed
27. efficacy 3 minute stair climb test [ Time Frame: 30 months post gene therapy ]
    number of stair climbed
28. efficacy 3 minute stair climb test [ Time Frame: 36 months post gene therapy ]
    number of stair climbed

Eligibility Criteria

• Ages Eligible for Study: 4 Years to 65 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Subjects must have a documented biochemical and molecular diagnosis of MPS VI.
2. Subjects must be 4 years old or older.
3. Subjects should have received Enzyme Replacement Therapy (ERT) for at least 12 months before enrolment, and should continue to receive treatment until 7-14 days before IMP administration.
4. Documented informed consent; willingness to adhere to protocol and required long-term follow-up as evidenced by written informed consent.

Exclusion Criteria:

1. Subjects unable or unwilling to meet requirements of the study.
2. Participation in a clinical study with an investigational drug in the 6 months prior to enrolment in this trial.
3. Subjects who are unable to perform the 6MWT.
4. History of severe anaphylactoid reaction to Naglazyme in subjects receiving ERT that could affect the safety (severe reaction is meant to be an event with respiratory impairment that is life-threatening).
5. Presence of tracheostomy or need of ventilatory assistance.
6. Subjects with evidence of progressive severe myelomalacia that is predicted to require neck surgery in the first six months after enrolment.
7. Serum AST or ALT above the upper limit of normal range at the baseline evaluations (Baseline 2, -5 days).
8. Co-existence of chronic diseases or clinically relevant abnormal baseline laboratory values; infections with hepatitis B, C, or HIV (Baseline 1).
9. Systemic corticosteroid therapy or other immunosuppressive/immunomodulating drugs within 2 weeks prior to IMP administration.
10. Female individuals of childbearing age who are pregnant or nursing or unwilling to use effective contraception for at least one year post- IMP administration.
11. Fertile male individuals who are unwilling to use male barrier contraceptives such as condom.
12. 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.
13. Detectable serum neutralizing antibodies (NAB) against AAV8 vector (Baseline 1).

Contacts and Locations

Contacts

Contact: Nicola Brunetti-Pierri; +390817463288; nicola.brunetti@unina.it

Locations

Italy

Federico II University; Recruiting

Napoli, Naples, Italy, 80131

Contact: Nicola Brunetti-Pierri +390817463288 brunetti@tigem.it

Netherlands

Erasmus Medical Center, Rotterdam Center for Lysosomal and Metabolic disease; Recruiting

Rotterdam, Netherlands

Contact: Ans van der Ploeg a.vanderploeg@erasmusmc.nl

Turkey

Children's Hospital Hacettepe University; Recruiting

Ankara, Turkey

Contact: Serap Sivri ssivri@hacettepe.edu.tr

Sponsors and Collaborators

Fondazione Telethon

Investigators

• Principal Investigator: Nicola Brunetti-Pierri; Fondazione Telethon

More Information

• Responsible Party: Nicola Brunetti-Pierri, Principal Investigator, Fondazione Telethon
• ClinicalTrials.gov Identifier: NCT03173521 History of Changes
• Other Study ID Numbers: TIGEM1-MPS VI
• First Posted: June 2, 2017
• Last Update Posted: January 25, 2019
• Last Verified: January 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Mucopolysaccharidoses; Mucopolysaccharidosis VI; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Metabolic Diseases