title: Intracerebral administration of adeno-associated viral vector serotype rh.10 carrying human SGSH and SUMF1 cDNAs in children with mucopolysaccharidosis type IIIA disease: results of a phase I/II trial.
abstract: Mucopolysaccharidosis type IIIA is a severe degenerative disease caused by an autosomal recessive defect of a gene encoding a lysosomal heparan-N-sulfamidase, the N-sulfoglycosamine sulfohydrolase (SGSH), the catalytic site of which is activated by a sulfatase-modifying factor (SUMF1). Four children (Patients 1-3, aged between 5.5 and 6 years; Patient 4 aged 2 years 8 months) received intracerebral injections of an adeno-associated viral vector serotype rh.10-SGSH-IRES-SUMF1 vector in a phase I/II clinical trial. All children were able to walk, but their cognitive abilities were abnormal and had declined (Patients 1-3). Patients 1-3 presented with brain atrophy. The therapeutic vector was delivered in a frameless stereotaxic device, at a dose of 7.2×10(11) viral genomes/patient simultaneously via 12 needles as deposits of 60 μl over a period of 2 hr. The vector was delivered bilaterally to the white matter anterior, medial, and posterior to the basal ganglia. Immunosuppressive treatment (mycophenolate mofetil and tacrolimus) was initiated 15 days before surgery and maintained for 8 weeks (mycophenolate mofetil) or throughout follow-up (tacrolimus, with progressive dose reduction) to prevent elimination of transduced cells. Safety data collected from inclusion, during the neurosurgery period and over the year of follow-up, showed good tolerance, absence of adverse events related to the injected product, no increase in the number of infectious events, and no biological sign of toxicity related to immunosuppressive drugs. Efficacy analysis was necessarily preliminary in this phase I/II trial on four children, in the absence of validated surrogate markers. Brain atrophy evaluated by magnetic resonance imaging seemed to be stable in Patients 1 and 3 but tended to increase in Patients 2 and 4. Neuropsychological evaluations suggested a possible although moderate improvement in behavior, attention, and sleep in Patients 1-3. The youngest patient was the most likely to display neurocognitive benefit.
authors: 1 Pediatric Neurology, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud , Le Kremlin Bucêtre 94275, France .
authors: Marc
authors: M
authors: Tardieu
authors: Michel
authors: M
authors: Zérah
authors: Béatrice
authors: B
authors: Husson
authors: Stéphanie
authors: S
authors: de Bournonville
authors: Kumaran
authors: K
authors: Deiva
authors: Catherine
authors: C
authors: Adamsbaum
authors: Fanny
authors: F
authors: Vincent
authors: Michael
authors: M
authors: Hocquemiller
authors: Christine
authors: C
authors: Broissand
authors: Valérie
authors: V
authors: Furlan
authors: Andrea
authors: A
authors: Ballabio
authors: Alessandro
authors: A
authors: Fraldi
authors: Ronald G
authors: RG
authors: Crystal
authors: Thomas
authors: T
authors: Baugnon
authors: Thomas
authors: T
authors: Roujeau
authors: Jean-Michel
authors: JM
authors: Heard
authors: Olivier
authors: O
authors: Danos
mesh_terms: D002552:Cerebral Ventricles / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D007276:Injections, Intraventricular; D008297:Male; D009084:Mucopolysaccharidosis III / Q000628:therapy*; D050862:Oxidoreductases Acting on Sulfur Group Donors; D013429:Sulfatases / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D050862:Oxidoreductases Acting on Sulfur Group Donors; D006867:Hydrolases; C480483:SUMF1 protein, human; D013429:Sulfatases; C022708:N-sulfoglucosamine sulfohydrolase