Gene therapy for Canavan disease slows brain atrophy and stabilizes patients' clinical condition, show findings that highlight the need for very early diagnosis and intervention.
There were 28 patients in the study, 13 of whom received an adeno-associated viral vector carrying the aspartoacylase gene via intraparenchymal delivery at six brain infusion sites. Patients with Canavan disease have defective aspartoacylase, leading to build-up of N-acetyl-aspartate (NAA) in the brain, degeneration of white matter, and, usually, early mortality.
The patients ranged in age from 4 to 83 months at the time of treatment. Paola Leone (University of Medicine & Dentistry of New Jersey, Stratford, USA) and team followed them up for at least 5 years, and in some cases up to 10 years, after gene therapy, during which there were no adverse effects attributed to the treatment.
In untreated Canavan disease patients, NAA levels in the brain rose over time, whereas they significantly decreased in treated patients - in the frontal region of 11 patients and the periventricular, occipital, and basal ganglia regions of all patients.
In addition, magnetic resonance imaging findings indicated a return to "a more normal pattern of myelination" in several white matter tracts in 10 patients, although other tracts showed no improvement. Some patients had a partial stabilization or even reversal of brain atrophy, but others had progressive atrophy, particularly those with evidence of rapid increases in brain atrophy prior to gene therapy.
The patients had overall improvements on the Gross Motor Function Measure, but the team cautions that "despite observed clinical improvements, raw scores still fell within the range for patients severely affected by spastic quadriplegia."
There were also improvements in various measures in a physical exam that included neurologist and caregiver observations, most notably for alertness. But the three or four oldest patients (average 46 months at treatment) did not improve.
"Normalization of NAA at a very early age may be necessary to prevent irretrievable dysmyelination, motor delay, and mental retardation in Canavan disease," write Leone et al in Science Translational Medicine.
Patients who showed the largest improvement were treated before 2 years of age, they note, in line with findings in other neurometabolic diseases, in which the therapeutic window appears to close "a matter of weeks" after birth.
The researchers suggest that future gene therapy for Canavan disease should focus on children aged up to 3 months, in whom irreversible structural changes have not yet occurred. But they add: "Unfortunately, diagnosis typically does not occur until 12 months of age, after patients have already lost developmental milestones; thus, early diagnosis and intervention are essential."
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