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.
RATIONALE: To report long-term follow-up data describing frequency and quantity of home dosing of food allergens following desensitization with multi-OIT protocols as part of two previously published phase 1 clinical trials. METHODS: A total of 73 participants completed two single-center phase 1 trials evaluating the safety of OIT for multiple food allergens using a mOIT protocol (n543) or a rapid mOIT protocol with omalizimab (n530). In both trials, subjects were instructed to maintain daily dosing and if skin test for the allergen became negative, dosing was decreased. Participants returned yearly for follow-up food challenges. RESULTS: Long-term follow up data was available for 70 of 73 participants. The long-term follow-up period for participants who completed the mOIT protocol ranged from 18 to 73 months; 22 (56%) chose to consume 2g protein doses of each allergen, while 13 (33%) chose to consume between 300mg and 2g per allergen. In the rapid mOIT protocol, follow-up ranged from 11 to 46 months; 9 (30%) participants chose to consume 2g doses and 18 (60%) participants chose to consume doses between 300mg and 2g. All subjects in both groups remained desensitized to at least 2g protein of each of their food allergens on repeat food challenge, even those who chose to consume home doses as low as 300mg of their allergens three times per week. CONCLUSIONS: Subjects who completed a mOIT protocol continue to consume regular doses that maintain desensitization to 2g of each allergen.
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