ABSTRACT
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.
Subject(s)
Amidohydrolases/genetics , Brain , Canavan Disease/therapy , Clinical Protocols , Dependovirus/genetics , Genetic Therapy/methods , Genetic Vectors/administration & dosage , Amidohydrolases/deficiency , Amidohydrolases/metabolism , Brain/enzymology , Brain/pathology , Brain/physiopathology , Canavan Disease/pathology , Canavan Disease/surgery , Child, Preschool , Clinical Trials as Topic , Cohort Studies , Female , Follow-Up Studies , Gene Transfer Techniques , Genetic Vectors/therapeutic use , Humans , Infant , Injections, Intraventricular , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Male , Patient SelectionABSTRACT
A primary intracranial atypical teratoid/rhabdoid tumor was encountered in a child (age 4 years and 9 months) with Canavan disease. The tumor contained a large spindled cell component as well as classical rhabdoid morphology and focal areas resembling a primitive neuroectodermal tumor. The rhabdoid areas of the neoplasm were immunoreactive with antibodies against epithelial membrane antigen and vimentin, in the classically described pattern. Ultrastructurally these portions of the tumor displayed the characteristic perinuclear whorls of intermediate filaments reported in rhabdoid tumors of all body sites. Thought to be purely coincidental, this is also the first description of any intracranial neoplasm associated with Canavan disease.
