Mucopolysaccharidosis type IIIA is a severe degenerative disease due to an autosomal recessive genetic defect in the gene coding for the lysosomal N-sulfoglycosamine sulfohydrolase ( SGSH ) whose catalytic site is activated by a sulfatase modifying factor ( SUMF1 ).
Four children ( patient 1-3 close to 6 years of age, patient 4 was 2ye8m ) received intra-cerebral injection of an AAV- 2/rh.10-SGSH-IRES-SUMF1 vector in a phase I/II clinical trial.
All children were ambulatory but had already decreased cognitive abilities ( marked in P1-3, moderate in P4 ) and for P1-3, brain atrophy detectable on magnetic resonance images ( MRIs ).
The therapeutic vector was delivered at a dose of 7.2 • 1011 viral genomes/patient in 12 preplaned simultaneous frameless stereotaxic deposits ( 60ll ) in 2 hours, bilaterally within white matter anterior, medial and posterior to basal ganglia. I
n order to prevent elimination of transduced cells, an immunosuppressive treatment ( Mycophenolate mofetil, Tacrolimus ) was initiated 15 days before surgery and maintained either 8 weeks ( Mycophenolate mofetil ) or throughout the follow-up ( Tacrolimus, with progressive dose reduction ).
Safety data collected from inclusion, during the neurosurgery period and over the year of follow-up showed a good tolerance, a lack of adverse events related to AAV vector, no increase of infectious events and no biological sign of toxicity related to immunosuppressive drugs.
Efficacy analysis can only be preliminary in a phase I/II trial on 4 children and in absence of validated surrogate markers. However, neuropsychological evaluation suggested a possible improvement of behaviour, attention and sleep in P1-3 who showed cognitive decline before treatment.
Neurocognitive benefit ( motricity, language ) was more likely present in the youngest patient. ( Xagena )
Tardieu M et al, Human Gene Therapy, 2013