Xandra Breakefield, Ph.D.

Professor of Neurology

Massachusetts General Hospital - East
Neurogenetics Unit, CNY 6216
55 Fruit St
Boston, MA 02114
Telephone: 617-726-5728
Fax: 617- 724-1537
Email: breakefield@hms.harvard.edu
Lab web site: The Breakefield Lab
Predocs: 0 Postdocs: 3 Completed PhD's: 20

Our laboratory uses molecular genetic and imaging methods to gain insight into the molecular etiology of early onset torsion dystonia, and to develop vectors and strategies for gene therapy of brain tumors and neurologic diseases.

Torsion dystonia is a movement disorder characterized by contracted postures of the limbs and torso due to abnormal circuitry in the basal ganglia affecting sensori-motor communication. The mutant protein responsible for most early onset cases encodes torsinA, a AAA+ protein localized primarily in the endoplasmic reticulum (ER). This protein is expressed at highest levels in the perinatal period in neurons and appears to act as a chaperone protein involved in processing of proteins through the secretory pathway and linking the ER to the cytoskeleton. Current studies focus on identifying interacting partners for torsinA and determining how the mutant protein disrupts cell adhesion, neurite extension and synaptic communication.

Vectors derived from HSV, AAV and lentivirus are used to deliver therapeutic genes and imaging reporters in mouse models of inherited neurologic dieases, i.e. ataxia telangiectasia and neuronal ceroid lipofuscinosis, and brain tumors, including glioma xenografts and Cre-lox-induced loss of tumor suppressor genes, i.e. neurofibromatosis type 2 and tuberous sclerosis. Therapeutic strategies include expressing biotinylated docking sites on the cell surface to bind streptavidin-toxin conjugates using neuroprecursor cells to home to invasive tumor cells, and regulating microRNA levels to inhibit angiogenesis.

Selected References:

• Sharma N, Baxter M, Petravicz J, Bragg DC, Schienda A, Standaert D, and Breakefield XO (2005) Impaired motor learning in mice expressing torsinA with the DYT1 dystonia mutation J. Neurosci. 25:5351-5355.
• Shah K, Bureau E, Kim DE, Yang K, Tang Y, Weissleder R, Breakefield XO (2005) Glioma therapy and real-time imaging of neural precursor cell migration and tumor regression, Annals Neurol. 57:34-41.
• Hewett JW, Zeng J, Niland BP, Bragg DC, Breakefield XO (2006) Dystonia-causing mutant torsinA inhibits cell adhesion and neurite extension through interference with cytoskeletal dynamics, Neurobiol. Dis. 22:98-111.
• McKee TD, Grandi P, Mok W, Alexandrakis G, Insin N, Zimmer JP, Bawendi MG, Boucher Y, Breakefield XO and Jain R (2006) Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simlex virus vector, Cancer Res. 66:2509-2513.
• Tannous B, Grimm J, Perry K, Chen JW, Weisselder R, and Breakefield XO (2006) Metabolic biotinylation of cell surface receptors for tumor in vivo imaging, Nature Methods, 3:391-396.
• Jeong K-H, Bakowska J, Song IO, Fu N, Brekefield XO, and Kaiser U (2007) Improvement in reproductive parmeters in hypogonadal female mice by regulated replacement therapy in the central nervous system, Gene Ther., 14:1092-1101.
• Hewett JW, Tannous B, Niland BP, Nery FC, Zeng J, Li Y, Breakefield XO (2007) Mutant torsinA interferes with protein processing through the secretory pathway in DYT1 dystonia cells, Proc. Nat'l Acad. Sci U.S.A. 104:7271-7276.
• Sah K, Hingtgen S, Kasmieh R, Figueriredo JL, Garcia-Garcia E, Martinez-Serrano A, Breakefield XO, Weissleder R (2008) Bimodal viral vectors and in vivo imaging reveal the fate of human neural stem cells in experimental glioma model, J. Neurosci. 28:4406-4413.