Canavan disease is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the substrate N-acetylaspartate (NAA) in the brain. Accumulation of NAA results in spongiform degeneration of white matter and severe impairment of psychomotor development. The goal of this prospective cohort study was to assess long-term safety and preliminary efficacy measures after gene therapy with an adeno-associated viral vector carrying the ASPA gene (AAV2-ASPA). Using noninvasive magnetic resonance imaging and standardized clinical rating scales, we observed Canavan disease in 28 patients, with a subset of 13 patients being treated with AAV2-ASPA. Each patient received 9 × 1011 vector genomes via intraparenchymal delivery at six brain infusion sites. Safety data collected over a minimum 5-year follow-up period showed a lack of long-term adverse events related to the AAV2 vector. Posttreatment effects were analyzed using a generalized linear mixed model, which showed changes in predefined surrogate markers of disease progression and clinical assessment subscores. AAV2-ASPA gene therapy resulted in a decrease in elevated NAA in the brain and slowed progression of brain atrophy, with some improvement in seizure frequency and with stabilization of overall clinical status.

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SynopsisAn alcoholysis method is described for the modification of high molecular weight poly(p-benzyl L-asparatate) ; by this method the benzyl groups in the polypeptide have been replaced by methyl, ethyl, isopropyl, n-propyl, and phenethyl groups to give a series of copolymers of each of the corresponding aspartate esters with benzyl L-aspartate. By repeating the reactions, replacement of better than 99% has been achieved in some cases to give in effect the homopolymer. Optical rotatory dispersion studies show that of all the systems studied only poly(gmethy1 L-aspartate) has the left-handed helix sense, the others are right-handed. It is shown further that the helix sense is not an intrinsic property of the nature of the aspartate side chain. Raising t,he temperature of chloroform solutions of the right-handed form of the copolymers of benzyl L-aspartate and ethyl L-aspartate results in a transition to the left-handed helix, the temperature of the transition being dependent on the composition of the copolymer. Also poly(@-npropyl L-aspartate) undergoes a transition from the right-to the left-handed helix form a t 59°C. These results suggest a general pattern of behavior of poly(aspartate esters) and that with suitable conditions of solvent and temperature they may be in either the right-or lefi-handed helical form.

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To date, this article describes the largest reported series of ONSMs. Although longer follow-up is necessary, we think that CF-SRT represents a safe alternative to surgery and offers a higher likelihood of preserved or improved vision in patients with ONSM. Our analysis suggests that CF-SRT is also preferable to observation. Functional (111)In-octreotide single-photon emission computed tomographic scintigraphy provides a useful technique for the assessment of tumor control that complements serial posttreatment magnetic resonance imaging in patients with ONSMs.