Investigator, Full Prof (M) Neurology, Mass General Research Institute

Professor of Neurology Harvard Medical School

aavs; ataxia telangiectasia; diseases of the nervous system; dystonia musculorum deformans; early onset torsion dystonia; exosomes; gene therapy; gene therapy for brain tumors; gene transfer techniques; genes neurofibromatosis 2; genetic therapy; genetic vectors; glioblastoma; herpesvirus 1 human; lentivirus; molecular chaperones; molecular genetics; monoamine oxidase; simplexvirus; torsina; viral vectors

The Breakefield laboratory uses molecular genetic techniques to elucidate the etiology of inherited neurologic diseases and to develop vectors, which can deliver genes to the nervous system.

A plasmid-based amplicon vector derived from herpes simplex virus type 1 has been developed for non-toxic gene delivery to neural cells. This vector, which uses the herpes virion for gene delivery, can carry large transgenes (>150 kb), and has been modified to include elements that promote episomal retention or site-specific integration into the host cell genome. Further constructions are underway to incorporate inducible and cell-specific promoters to promote homologous recombination and to convert cells to vector-producing cells. These vectors are being tested in transgenic mouse models of ataxia telangiectasia, neurofibromatosis and lysosomal storage diseases and for brain tumor therapy to try to achieve correction of genetic defects and therapeutic intervention, respectively. Work is also underway to expand the range of gene delivery in vivo using migratory neuroprecursor cells and to image transgene expression in animals with MRI, bioluminescence and infrared sensitive reporters.

Through positional cloning efforts this laboratory has identified the gene responsible for a severe form of dystonia characterized by contracted posturing of the limbs and torso starting in childhood. The responsible protein, torsinA, has homology to the AAA+ class of chaperone proteins, which have a variety of functions including protection from cellular stress and vesicle transport/fusion. Immunocytochemistry, yeast two-hybrid screens, and inducible cell expression are being used to study the ER localization and function of this protein, as well as the nature of whorled membrane inclusions formed by the dominant-negative mutant protein.