Intracerebral Gene Therapy for Children With Early Onset Forms of Metachromatic Leukodystrophy

Metachromatic Leukodystrophy Clinical Trial

— TG-MLD  

Official title:

A Phase I/II, Open Labeled, Monocentric Study of Direct Intracranial Administration of a Replication Deficient Adeno-associated Virus Gene Transfer Vector Serotype rh.10 Expressing the Human ARSA cDNA to Children With Metachromatic Leukodystrophy.

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01801709
• Other study ID #: C11-09
• Secondary ID: 2011-004410-42
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: June 2014
• Est. completion date: May 2029

Study information

• Verified date: January 2022
• Source: Institut National de la Santé Et de la Recherche Médicale, France
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The objective of this open-label, single arm, monocentric, phase I/II clinical study is to assess safety and efficacy of ARSA gene transfer in the brain of children affected with early onset forms of Metachromatic Leukodystrophy (MLD). For this purpose, an adeno-associated virus serotype rh.10 (AAVrh.10) vector will be used to transfer the ARSA cDNA coding for Arylsulfatase A (ARSA) enzyme into the brain of children. Five patients with early onset form of MLD, age ranging from 6 months to 4 years, will be included in this protocol and will be followed during 24 months. Patients will be selected at presymptomatic or early stage of their disease, following clinical, neuropsychological and brain imaging criteria. Twelve simultaneous injections of the investigational medicinal product will be performed in the white matter of both brain hemispheres, through 6 image-guided tracks, with 2 deposits per track. A low dose (1x10EXP12 vg total) will be administered to the first 2 patients, while the last 3 will receive a higher dose (4x10EXP12 vg total). Safety and efficiency will be evaluated based on clinical, neuropsychological, radiological, electrophysiological and biological parameters.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 5
• Est. completion date: May 2029
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 5 Years

Eligibility

Inclusion Criteria:

• Boys or girls with an early onset form of MLD.
• Age between 6 months and 5 years, inclusive
• Diagnostic of MLD based on the measurement of ARSA activity in leukocytes and the accumulation of sulfatides in urine, along with normal activity of at least one other sulfatase
• Informed consent signed up and willingness for monitoring 2 years after treatment.
• Normal values for standard laboratory tests

Exclusion Criteria:

• Absence of ARSA protein by immunocytochemistry and/or ELISA
• Gestational age <32 weeks of amenorrhoea and age < 1 year
• Brain atrophy with a subdural space > 10 mm in the frontal region
• Performance IQ<50 at WPPSI-III or cognitive function < 3rd percentile at the Bayley's test of infant development
• If age > 16 months at inclusion, inability to walk few steps alone OR inability to walk few steps with support on one side along with inability to stand up alone
• Impossibility for anesthesia
• Malignancy, cardiac malformation, liver dysfunction, or renal dysfunction
• Neurological disorder, except benign, not related to MLD.
• Any other clinically significant untreated co-morbid medical condition as determined by the clinical investigator, including cardiac, pulmonary or kidney disease.
• MRI impossibility
• Evoked potential impossibility
• Participation to another therapeutic clinical trial for MLD.
• Unaffiliated to any French or any other National Health Insurance.

Related Conditions & MeSH terms

• Leukodystrophy, Metachromatic
• Metachromatic Leukodystrophy

Intervention

Genetic:
• intracerebral administration of AAVrh.10cuARSA

Locations

Country	Name	City	State
France	Bicêtre Hospital - Paris Sud	Le Kremlin-Bicêtre

Sponsors (3)

Lead Sponsor	Collaborator
Institut National de la Santé Et de la Recherche Médicale, France	Assistance Publique - Hôpitaux de Paris, European Leukodystrophy Association

Country where clinical trial is conducted

France, 

References & Publications (4)

Colle MA, Piguet F, Bertrand L, Raoul S, Bieche I, Dubreil L, Sloothaak D, Bouquet C, Moullier P, Aubourg P, Cherel Y, Cartier N, Sevin C. Efficient intracerebral delivery of AAV5 vector encoding human ARSA in non-human primate. Hum Mol Genet. 2010 Jan 1;19(1):147-58. doi: 10.1093/hmg/ddp475. — View Citation

i Dali C, Hanson LG, Barton NW, Fogh J, Nair N, Lund AM. Brain N-acetylaspartate levels correlate with motor function in metachromatic leukodystrophy. Neurology. 2010 Nov 23;75(21):1896-903. doi: 10.1212/WNL.0b013e3181feb217. — View Citation

Piguet F, Sondhi D, Piraud M, Fouquet F, Hackett NR, Ahouansou O, Vanier MT, Bieche I, Aubourg P, Crystal RG, Cartier N, Sevin C. Correction of brain oligodendrocytes by AAVrh.10 intracerebral gene therapy in metachromatic leukodystrophy mice. Hum Gene Ther. 2012 Aug;23(8):903-14. doi: 10.1089/hum.2012.015. Epub 2012 Jul 23. — View Citation

Sondhi D, Johnson L, Purpura K, Monette S, Souweidane MM, Kaplitt MG, Kosofsky B, Yohay K, Ballon D, Dyke J, Kaminksy SM, Hackett NR, Crystal RG. Long-term expression and safety of administration of AAVrh.10hCLN2 to the brain of rats and nonhuman primates for the treatment of late infantile neuronal ceroid lipofuscinosis. Hum Gene Ther Methods. 2012 Oct;23(5):324-35. doi: 10.1089/hgtb.2012.120. Epub 2012 Nov 6. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Evaluate the tolerance of the intracerebral administration of a single dose of AAVrh.10cuARSA	Tolerance will be measured by : Adverse event,; Clinical and neurological exams,; Laboratory tests,; Neuroimagery (CT scan, brain MRI).	During the two years follow-up
Secondary	Evaluate the efficacy of intracerebral administration of a single dose of AAVrh.10cuARSA to stop the disease progression.	Efficacy will be measured by: MLD neurological severity score,; Neurological evaluation,; Motor scores (GMFM, Ashworth and ICARS),; Cognitive functions (Bayley Scales of Infant Development (BSID)(0-42 months), or Wechsler Preschool and Primary Scale of Intelligence-III (WPPSI-III) (43 months-6 years)),; MLD severity MRI score, MRI-DTI parameters, measurement of cerebral atrophy and spectroscopy,; Neuroelectrophysiological tests (peripheral nerve conduction velocity, visual, auditory and somatosensory evoked potentials).	During the two years follow-up