Intracerebral Gene Therapy in Children With Sanfilippo Type B Syndrome

Protocol AMT110-CD-001: A Phase I/II, Open-label, Study of Intracerebral Administration of Adeno-associated Viral Vector Containing the Human Alpha-N-acetylglucosaminidase cDNA in Children With Sanfilippo Type B Syndrome

This is an open-label, phase I/II study of intra-cerebral administration of adenovirus-associated viral vector containing the human NAGLU cDNA to children suffering from Sanfilippo type B syndrome.

Study Overview

• Status: Completed
• Conditions: Sanfilippo Syndrome B
• Intervention / Treatment: Drug: rAAV2/5-hNAGLU

Detailed Description

This is an open-label, phase I/II study of intra-cerebral administration of adenovirus-associated viral vector containing the human NAGLU cDNA to children suffering from Sanfilippo type B syndrome.

Four patients, 18 months up to the 5th birthday, have been included.

The inclusion period will be 8 to 12 months. The duration of follow-up for each patient is 1 year post-surgery. The duration of the first extension phase is 18 months. The duration of the second extension phase is 36 months. Therefore, the maximum time of the follow-up will be 66 months

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Le Kremlin-Bicetre Cedex
    • Paris, Le Kremlin-Bicetre Cedex, France, 94275
      • Hopitaux Universitaires Paris-Sud

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 5 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Age: 18 months up to 60 months (5th birthday);
• Onset of clinical manifestations related to mucopolysaccharidosis type IIIB (MPSIIIB);
• NAGLU activity in peripheral blood cell and/or cultured fibroblast extracts of less than 10% of controls;
• Patient affiliated to, or covered by a French social security regimen, or European patients with European Health Insurance Card;
• Family understanding the procedure and the informed consent;
• Signed informed consent by both parents or legal representative;
• Vital laboratory parameters within normal range.

Exclusion Criteria:

• Presence of brain atrophy on baseline MRI judged on a cortico-dural distance of more than 0.6 cm;
• Any condition that would contraindicate general anesthesia;
• Any other permanent medical condition not related to MPSIIIB that could contraindicate the study participation;
• No independent walking (ability to walk without help);
• Any medication aiming at modifying the natural course of MPSIIIB given during the 6 months before vector injection (sleep and mood regulators are accepted);
• Any condition that would contraindicate treatment with Modigraf®, Cellcept® and prednisolone (Solupred® and Solumedrol®).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: rAAV2/5-hNAGLU; Each patient will receive 960 µL of vector suspension. The vector suspension will be deposited simultaneously at 16 sites, each deposit containing 2.4x 1011 vg (4x1012 vg in total).	Drug: rAAV2/5-hNAGLU; one-time brain intraparenchymal gene therapy dose; Other Names: AAV5

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Related (Serious) Adverse Events as assessed by continuous evaluation of change from baseline	Multiple measurements will be aggregated to derive the number of participants with Abnormal Laboratory Values and/or Adverse Events that are related to Treatment.	Baseline until end of study (Month 66)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with presence of brain atrophy, white matter lesions and other lesions as assessed by cerebral MRI	MRIs at Baseline, Month 3, Month 12, Month 30, Month 48 and last visit Month 66. Cerebral MRI will be collected for safety assessment to retrospectively evaluate for efficacy at Baseline, D0, Month 3, Month12, Month 30 and last visit Month 66.	Baseline until end of study (Month 66)

Collaborators and Investigators

• Sponsor: UniQure Biopharma B.V.
• Collaborators: Institut Pasteur; Venn Life Sciences
• Investigators: Principal Investigator: Kumaran Deiva, MD, Hopitaux Universitaires Paris-Sud

Publications and helpful links

General Publications

• Gougeon ML, Poirier-Beaudouin B, Ausseil J, Zerah M, Artaud C, Heard JM, Deiva K, Tardieu M. Cell-Mediated Immunity to NAGLU Transgene Following Intracerebral Gene Therapy in Children With Mucopolysaccharidosis Type IIIB Syndrome. Front Immunol. 2021 May 10;12:655478. doi: 10.3389/fimmu.2021.655478. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (Actual): September 17, 2013
• Primary Completion (Actual): November 27, 2019
• Study Completion (Actual): November 27, 2019

Study Registration Dates

• First Submitted: June 15, 2016
• First Submitted That Met QC Criteria: October 2, 2017
• First Posted (Actual): October 3, 2017

Study Record Updates

• Last Update Posted (Actual): December 2, 2019
• Last Update Submitted That Met QC Criteria: November 28, 2019
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Disease; Genetic Diseases, Inborn; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Mucopolysaccharidoses; Syndrome; Mucopolysaccharidosis III
• Other Study ID Numbers: AMT110-CD-001