Gene Therapy of Canavan Disease: AAV-2 Vector for Neurosurgical Delivery of Aspartoacylase Gene (ASPA) to the Human Brain

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.

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

“…Based on the assumption that the primary etiology of Canavan disease involves toxic NAA concentration increases in the brain (Leone et al, 1999), possibly causing osmotic dysregulation and intramyelinic water accumulation, adenoviral transfer of the ASPA gene to the brains of humans has been performed in an to attempt to reverse brain edema and vacuolation (Janson et al, 2002;Leone et al, 2000). No follow up studies showing significant myelination or motor improvements in these children have been published to date, so it is difficult to assess to what extent any pathologies were ameliorated.…”

AAV2-mediated CLN2 gene transfer to rodent and non-human primate brain results in long-term TPP-I expression compatible with therapy for LINCL

“…There is currently favorable short-term safety data related to the intracranial transfer of AAV2 CU hCLN2 in human patients based upon the growing clinical experience of AAV2-mediated gene transfer to the brain for the treatment of Canavan and Parkinson's diseases. 42,43 Therefore, it seems likely that there would be no significant safety issues related to intracranial transfer of AAV2 CU hCLN2 in human patients. In this context, LINCL is a candidate disease for further preclinical development of AAV2-mediated gene therapy.…”

Development of efficient plasmid DNA transfer into adult rat central nervous system using microbubble-enhanced ultrasound

“…In fact, novel gene therapy has been tried clinically for glioblastoma, 1,2 Parkinson's disease, 3 and Canavan's disease. 4 In these trials, adenovirus and adeno-associated virus (AAV) were commonly used. However, there are serious safety problems in the case of viral vectors, such as immunogenicity, 5 delayed demyelination, 6 and difficulties in the preparation of a high titer of virus.…”