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

Marc Tardieu, Michel Zérah, Béatrice Husson, Stéphanie De Bournonville, Kumaran Deiva, Catherine Adamsbaum, Fanny Vincent, Michael Hocquemiller, Christine Broissand, Valérie Furlan, Andrea Ballabio, Alessandro Fraldi, Ronald Crystal, Thomas Baugnon, Thomas Roujeau, Jean Michel Heard, Olivier Danos

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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 7.2×1011 viral genomes/patient simultaneously via 12 needles as deposits of 60 μl over a period of 2hr. 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.

Original languageEnglish
Pages (from-to)506-516
Number of pages11
JournalHuman Gene Therapy
Volume25
Issue number6
DOIs
Publication statusPublished - 1 Jun 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Tardieu, M., Zérah, M., Husson, B., De Bournonville, S., Deiva, K., Adamsbaum, C., Vincent, F., Hocquemiller, M., Broissand, C., Furlan, V., Ballabio, A., Fraldi, A., Crystal, R., Baugnon, T., Roujeau, T., Heard, J. M., & Danos, O. (2014). 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. Human Gene Therapy, 25(6), 506-516. https://doi.org/10.1089/hum.2013.238