Miguel Sena-Esteves, Ph.D.
Neuroscience Center at Massachusetts General Hospital

Massachusetts General Hospital – East
Building 149
13th Street
Charlestown, MA 02129

Biography
Dr. Sena-Esteves received his Ph.D. from the University of Porto, Portugal. He came to the MGH as a research student in 1994 and is currently a member of the MGH faculty.

Research Program
This laboratory focuses on devising gene delivery approaches for treatment of neurodegenerative diseases, with special emphasis on GM1-gangliosidosis and Huntington’s disease, and tumors of the nervous system such as glioblastomas, meningiomas (CNS), and Schwannomas (PNS). The unifying concept behind the research in all these mechanistically distinct diseases is that an effective treatment will require widespread delivery of therapeutic genes to the brain, or the precise targeting of therapeutic agents to peripheral nervous system tumors.

Recombinant adeno-associated virus (AAV) vectors have proven to be among the most effective vectors for gene delivery to the CNS by transducing neurons efficiently, distribute widely under certain infusion conditions, and mediate long-term gene expression without any signs of toxicity or immune response. In addition to the identification of a variety of AAV serotypes with different tissue specificities, the AAV capsid can be modified to target specific cell surface receptors.

Five different lines of research using AAV vectors are in progress or in the development phase in the laboratory:

1. Investigate different infusion parameters and AAV designs to achieve global distribution of marker genes throughout the central nervous system after intra-ventricular or intravascular delivery.
   
2. Therapeutic studies in a GM1-gangliosidosis mouse model after delivery of AAV vectors in neonates or adult mice – characterization of biochemical, pathological, and behavioral parameters at different time points after AAV infusion. Progress to pre-clinical studies in large animal models of GM1-gangliosidosis.
   
3. Evaluate the effectiveness of expressing Huntingtin-specific iRNAs alone or in combination with different polyglutamine-aggregation modifier proteins in delaying or preventing disease progression in animal models of Huntington’s disease.
   
4. Investigate the possibility of creating zones of resistance to brain tumors in the adult CNS after delivery of AAV vectors encoding different therapeutic molecules.
   
5. Develop AAV vectors physically and genetically targeted to meningiomas or Schwannomas using differential microarray analysis of gene expression in these tumors.
   

Publications
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• Teixeira CA, Sena-Esteves, M., Lopes L, Sa Miranda MC, Ribeiro MG (2001). Retrovirus-Mediated Transfer and Expression of beta-Hexosaminidase alpha-Chain cDNA in Human Fibroblasts from GM2-Gangliosidosis B1 Variant. Hum Gene Ther. 12:1771-1783.
  
• Hsich G, Sena-Esteves, M., Breakefield XO. (2002). Critical issues in gene therapy for neurologic disease. Hum Gene Ther. 13:579-604.
  
• Sena-Esteves, M., Hampl, J.A., Camp, S.M., and Breakefield, X.O. (2002). Generation of stable retrovirus packaging cell lines after transduction with HSV/AAV/Retrovirus hybrid amplicons.. J. Gene Med. 4: 229-239
  
• Lim FY, Martin BG, Sena-Esteves, M., Radu A, Crombleholme TM. (2002). Adeno-associated virus (AAV)-mediated gene transfer in respiratory epithelium and submucosal gland cells in human fetal tracheal organ culture. J Pediatr Surg. 37: 1051-1057.
  
• Kaye EM, Sena-Esteves, M. (2002) Gene therapy for the central nervous system in the lysosomal storage disorders. Neurol Clin. 20: 879-901.
  
• MacKenzie TC, Kobinger GP, Kootstra NA, Radu A, Sena-Esteves, M., Bouchard S, Wilson JM, Verma IM, Flake AW. (2002). Efficient transduction of liver and muscle after in utero injection of lentiviral vectors with different pseudotypes. Mol Ther. 6: 349-58.
  
• Hampl, J.A., Camp, S.M., Mydlarz, W. K., Hampl, M., Ichikawa, T., Chiocca, E.A., Louis, D.N., Sena-Esteves, M., and Breakefield, X.O. (2003): Potentiated gene delivery to tumors using herpes simplex virus/ Epstein-Barr virus/RV tribrid amplicon vectors. Human Gene Therapy, 14:611-626.