Long-term follow-up after gene therapy for canavan disease.

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-acetyl-aspartate (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 × 10(11) 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.

Lithium citrate reduces excessive intra-cerebral N-acetyl aspartate in Canavan disease.

Our group has previously reported the first clinical application of lithium in a child affected by Canavan disease. In this study, we aimed to assess the effects of lithium on N-acetyl aspartate (NAA) as well as other end points in a larger cohort. Six patients with clinical, laboratory and genetic confirmation of Canavan disease were recruited and underwent treatment with lithium. The battery of safety and efficacy testing performed before and after sixty days of treatment included Gross Motor Function Testing (GMFM), Magnetic Resonance Imaging (MRI) Proton Magnetic Spectroscopy (H-MRS) as well as blood work. The medication was safe without any clinical or laboratory evidence for toxicity. Parental reports indicated improvement in alertness and social interactions. GMFM did not show statistically significant improvement in motor development. H-MRS documented an overall drop in NAA which was statistically significant in the basal ganglia. T1 measurements recorded on MRI studies suggested a mild improvement in myelination in the frontal white matter after treatment. Diffusion Tensor Imaging was available in two patients and suggested micro-structural improvement in the corpus callosum. The results suggest that lithium administration may be beneficial in patients with Canavan disease.

Mild-onset presentation of Canavan's disease associated with novel G212A point mutation in aspartoacylase gene.

We describe two sisters with a mild-onset variant of Canavan's disease who presented at age 50 and 19 months with developmental delay but without macrocephaly, hypotonia, spasticity, or seizures. Remarkably, both patients had age-appropriate head control, gross motor development, and muscle tone. There were very mild deficits in fine motor skills, coordination, and gait. Both sisters had a history of strabismus, but otherwise vision was normal. The older child showed evidence of mild cognitive and social impairment, whereas language and behavior were normal for age in the infant. Both patients were found to be compound heterozygotes for C914A (A305E) and G212A (R71H) mutations in ASPA. Like all other known ASPA mutations, this previously unknown G212A mutation appears to have low absolute enzyme activity. Nevertheless, it is associated in these patients with an extremely benign phenotype that is highly atypical of Canavan's disease. Biochemical and clinical data were evaluated using a generalized linear mixed model generated from 25 other subjects with Canavan's disease. There were statistically significant differences in brain chemistry and clinical evaluations, supporting a distinct variant of Canavan's disease. Future studies of ASPA enzyme structure and gene regulation in these subjects could lead to a better understanding of Canavan's pathophysiology and improvements in ASPA gene therapy.

Acute pancreatitis in children from Valproic acid: case series and review.

Valproic acid (VPA) is a commonly prescribed medication approved for use in the United States for epilepsy, migraine, and bipolar disorder. Although the common adverse effects associated with VPA are typically benign, less common but more serious adverse effects can occur. These include hepatotoxicity, teratogenicity, possible polycystic ovaries with the potential for sterility or carcinogenesis, and pancreatitis. A characteristic clinical profile has been determined for several of these adverse effects. We report four children with VPA-induced pancreatitis, one of which was fatal, and review the literature. Three of these children presented within a 4-year period (1995-1999) at the same institution. Because previous reviews have included either a small number of patients, or both pediatric and adult patients, we reviewed only pediatric cases to minimize any effect from adults with more serious co-existing medical illnesses. We attempted to determine the following: (1) if there are any characteristics that are predictive of pancreatitis and whether it will be fatal; (2) whether different clinical and laboratory characteristics exist for nonfatal vs fatal cases; and (3) if a specific pediatric patient profile, similar to that with VPA associated hepatotoxity or polycystic ovary-androgenism syndrome, could be identified.

Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain.

This clinical protocol describes virus-based gene transfer for Canavan disease, a childhood leukodystrophy. Canavan disease, also known as Van Bogaert-Bertrand disease, is a monogeneic, autosomal recessive disease in which the gene coding for the enzyme aspartoacylase (ASPA) is defective. The lack of functional enzyme leads to an increase in the central nervous system of the substrate molecule, N-acetyl-aspartate (NAA), which impairs normal myelination and results in spongiform degeneration of the brain. No effective treatment currently exists; however, virus-based gene transfer has the potential to arrest or reverse the course of this otherwise fatal condition. This procedure involves neurosurgical administration of approximately 900 billion genomic particles (approximately 10 billion infectious particles) of recombinant adeno-associated virus (AAV) containing the aspartoacylase gene (ASPA) directly to affected regions of the brain in each of 21 patients with Canavan disease. Pre- and post-delivery assessments include a battery of noninvasive biochemical, radiological, and neurological tests. This gene transfer study represents the first clinical use of AAV in the human brain and the first instance of viral gene transfer for a neurodegenerative disease.