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Intracerebral administration of AAV rh.10 carrying human SGSH and SUMF1 cDNAs in children with MPSIIIA disease: results of a phase I/II trial.

著者 Tardieu M , Zerah 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 JM , Danos O
Hum Gene Ther.2014 Feb 13 ; ():.
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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, all between 5.5 and 6 years of age, Patient 4=2years 8months) received intracerebral injections of an AAVrh.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 7.2x1011 viral genomes/patient simultaneously via 12 needles as deposits of 60l over a period of 2 hours. 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 eight weeks (mycophenolate mofetil) or throughout follow-up (tacrolimus, with progressive dose reduction) to prevent transduced cells elimination. Safety data collected from inclusion, during the neurosurgery period and over the year of follow-up showed good tolerance, an 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 MRI imaging seemed to be stable in Patients 1 and 3 but tended to increase in Patients 2 and 4. Neuropsychological evaluations suggested a possible albeit moderate improvement in behavior, attention and sleep in Patients 1-3. The youngest patient was the most likely to display neurocognitive benefit.
PMID: 24524415 [PubMed - as supplied by publisher]
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