Harvard University/McLean Hospital

Ole Isacson, M.D., leads the Udall Center at Harvard University Medical School and McLean Hospital in Belmont, Massachusetts. His team studies several novel treatments for Parkinson's disease in animal models. One project evaluates the ability of a new compound with neuroprotective properties to prevent and reverse parkinsonism in primates. Another project expands on tissue implantation research. Previous implantation investigations have been limited to single transplants into the part of the brain called the striatum. Dr. Isacson's group uses a primate model to examine the effect of multiple fetal or stem cell implants into the striatum and the substantia nigra and subthalamic nucleus, other areas of the brain that are affected by the dopamine loss characteristic of Parkinson's disease. They also transplant embryonic mouse tissue into rodent and primate Parkinson's models. Behavioral measurements, imaging studies using PET and magnetic resonance spectroscopy, and post-mortem tissue studies are used to evaluate the efficacy of the therapies. Benefits seen in any of these animal studies could lead to clinical trials in humans with Parkinson's disease.

Novel Therapeutic Approaches for Parkinson's Diseases

There are compelling research opportunities for Parkinson's Disease (PD) therapies. While L-dopa provides initial relief, there is a need for alternative strategies to deal with the continued loss of dopaminergic (DA) neurons, axons and terminals. We have a functional collaborative scientific group centered at McLean Hospital and Harvard Primate Center that investigates neuroprotective, neuromodulatory and cell therapy approaches for PD. We use animal models, including MPTP-treated animals with loss of dopamine cells, synapses and function. This Center is organized with 3 Cores that serve this and other NIH PD Centers, and 3 specific Projects that explore the shared theme of "Novel Therapeutic Approaches for Parkinson's Disease".

The Harvard University/McLean Hospital Udall Parkinson's Disease Research Center of Excellence:

Project 1. Functional differences between dopamine (DA) neurons in the substantia nigra (A9) that are vulnerable to PD compared to those spared in the same midbrain tissue region A10 (VTA) are examined. We discovered new gene and molecular candidates for neuroprotection by specific laser-capture and genomic analysis of characteristic DA neurons, now tested systematically by tissue culture and animal models to identify new pathways and substances providing insights into the pathogeneses and novel therapies for PD. Project 1 links to NIH Udall Centers, including specific collaborations with Duke U Udall Center for genomic convergence analysis of PD susceptibility genes from bioinformatics, linkage analysis and finally functional tests in our PD model systems.

Project 2. Post-mitotic but immature DA neurons are derived from primate and human stem cells for restorative transplantation into sophisticated PD model primates (including functional tests and imaging - see Core B). Project 2 works with collaborators and NIH Udall Centers, and like Project 1 and 3 is internally served by Core A, B and C, and specifically by its transplantation in PD primate models linked to the supply of genetically engineered human stem cells produced in Project 3.

Project 3. Specific midbrain genes and transcription factors controlling DA neuron development are identified and engineered into mouse and human stem cells. The resulting DA neurons are tested for functional repair in PD models in collaborative experiments in the Center. By using combinations of factors, a large fraction of stem cell derived cultured TH-positive GFP labeled and midbrain mouse or human neurons are sorted for purity and safety by the Center's advanced FACS technology before transplantation.

This PD Center also provides significant PD research education and training for scientists, and service to the PD patient and medical research communities. The Center's 3 research projects and its integrated Administrative Core (Core A), Functional Imaging Core (Core B) and a Clinical Transplantation, Bioinformatics, Human and Stem Cell Marker Core (Core C) are unique components in the NIH Udall Center of Excellence Consortium. The Harvard-McLean NIH Parkinson's Disease Research Center of Excellence provides a specialized environment for synergistic PD research on stem cell derived therapies, novel insights into functional genetic analysis of vulnerability of midbrain DA neurons and cutting edge research of new modalities leading to novel treatments for PD patients.

PUBLICATIONS FROM PD CENTER GRANT WORK: (1999-2006, 7 years)

1. Brownell et al. (1999) Biomedicine & Pharmacotherapy 53, 131-140.
2. Chen et al. (1999) Neuroreport 10, 2881-2886.
3. Isacson et al. (1999) In: Central Nervous System Diseases, pp. 187-207.
4. Isacson, O. (1999) Brain Pathol. 9, 495-498.
5. Costantini, L.C. and Isacson, O. (1999) In: Development of Dopamine Neurons, pp. 123-137.
6. Costantini et al. (1999) Human Gene Therapy 10, 2481-2494.
7. Costantini & Isacson (2000) Neuroscience 100, 515-520.
8. Costantini et al. (2000) Gene Therapy 7, 93-109.
9. Emilien et al. (2000) Monthly Journal of the Assoc of Physicians (UK) 93, 391-423.
10. Costantini and Isacson (2000) Exp Neurol 164, 60-70.
11. Bjorklund et al. (2000) Neuroscience News 6, 6-12.
12. Isacson et al. (2000) Parkinson's Disease and Related Disorders 7, 205-212.
13. Fink et al. (2000) Cell Transplant 9, 273-278.
14. Schumacher et al. (2000) Neurology 54, 1042-1050.
15. Costantini et al. (2001) Eur. J. Neurosci. 13, 1085-1092.
16. Holm et al. (2001) Neuroscience 104, 397-405.
17. Moore et al. (2001) Exp Neurol. 172, 363-376.
18. Hwang et al (2001) Human Gene Therapy 12, 1731-40.
19. McNaught et al. (2001) Nature Rev Neurosci 2, 589-594.
20. Isacson et al. (2001) Nat. Neurosci. 4, 553.
21. Isacson et al. (2001) In: Parkinson's Disease, Advances in Neurology, 86, 447-454.
22. Kang & Isacson (2001) In: Surgery for PD and Movement Disorders, pp. 235-244.
23. Kim et al. (2001) J. Neurochem 76, 280-294.
24. Williams-Johnson & Isacson (2001) Neurotoxicology 22, 855-858.
25. Chung et al. (2002) Stem Cells 20, 139-145.
26. Bjorklund et al. (2002) Proc Natl Acad Sci 99, 2344-2349.
27. Cicchetti et al. (2002) Eur J Neurosci 15, 991-998.
28. Seo et al. (2002) J. Neurochem. 80, 905-916.
29. Kim et al. (2002) Am J Med Genet 108, 140-147.
30. Costantini et al. (2002) Meth Mol Med., Gene Therapy Protocols 2nd Ed 69, 461-479.
31. Isacson, O. (2002) Brain Res Bulletin, 57, 839-846.
32. Brownell et al. (2002) Encyclopedia of Life Sciences, http://www.els.net
33. Bjorklund & Isacson (2002) Prog Brain Res 138, 411-420.
34. Pernaute et al. (2002) NeuroToxicology 23, 469-478.
35. Costantini & Isacson (2002) In: Immunosupp Analogs in Neuroprotection, pp. 49-66.
36. McNaught et al. (2002) Neurosci Lett 326, 155-158.
37. McNaught et al. (2002) Neuroreport 13, 1437-1441.
38. Cicchetti et al. (2002) Exp Neurol 177, 376-384.
39. Chung et al. (2002) Eur J Neurosci 16, 1829-1838.
40. McNaught et al. (2003) Exp Neurol. 179, 38-46.
41. Cicchetti et al. (2003) Xenotransplantation 10, 41-49.
42. Kim et al. (2003) J. Neurochem. 85, 622-34.
43. Isacson et al. (2003) Annals of Neurology, 53,135-48.
44. Isacson (2003) Lancet Neurology 2, 417-424.
45. Brownell et al. (2003) NeuroImage, 20, 1064-75.
46. Hwang et al. (2003) Brain Res Mol Brain Res 114,123-31
47. Sonntag et al. (2004) Eur. J. Neurosci. 19, 1141-52
48. Sanchez-Pernaute et al (2004) J Neuroinflammation 1, 6-14.
49. Jenkins et al. (2004) J. Neurosci. 24, 9553-60.
50. Cooper et al. (2004) J. Neurosci. 24, 8924-31.
51. Isacson et al. (2004) Parkinson Report, 15 (2) 6-8.
52. Isacson et al. (2004) Neuron 43, 165-8.
53. Isacson et al. (2004) In: Neurosci, Mol Med and the Therapeutic Transf of Neur 21, 357-73.
54. Chung et al. (2005) Mol Cell Neurosci 28, 241-52.
55. Sonntag et al. (2005) Mol Cell Neurosci 28, 417-29.
56. Lin et al. (2005) Mol. Cell Neurosci 28, 547-55.
57. Chung et al. (2005) Hum Mol Genet 14, 1709-25.
58. Mendez et al (2005) Brain 128, 1498-510.
59. Sánchez-Pernaute et al. (2005) Stem Cells 23, 914-22.
60. Kim et al. (2005) Stem Cells 24, 557-67.
61. Krichevsky et al. (2005) Stem Cells 24, 857-64.
62. Sonntag et al. (2005) Brain Res Mol Brain Res 134, 34-51.
63. Isacson et al. (2005) In: Neurodeg. Diseases: Neurobio, Pathogenesis and Therapeutics 24, 363-79.
64. Sánchez-Pernaute et al. (2005) Toxicol Appl Pharmacol 207, 251-6.
65. Isacson et al. (2006) In: Restorative Therapies in Parkinson's Disease pp 166-83.
66. Ferrari et al. (2006) Eur J Neurosci 2, 1885-96.
67. Chung et al. (2006) J Neurochem 97, 1467-80.
68. Chung et al. (2006) Stem Cells 24, 1583-93.
69. Lin et al. (2006) Stem Cells 24, 2504-13.
70. Kelly et al. (2006) Neuroscience 142, 343-54.
71. Ferrari et al. (2006) Eur J Neurosci 2, 1885-96.
72. Baker et al. (2006) J Comp Neurol 498, 747-61.
73. Sonntag et al. (2006) Stem Cells 25, 411-18.
74. Hedlund et al. (2007) Stem Cells 25, 1126-1135
75. Sánchez-Pernaute et al. (2007) Neurobiol Disease, in press
76. Vineula et al. "Transplantation of fetal ventral mesencephalic cell suspensions lacking dopamine transporter as a model of graft induced dyskinesias" abstract, World PD Congress 2006
77. Pruszak et al. "Profiling of surface antigen expression during mouse and human es cell-derived neurogenesis in vitro" abstract, ISSCR 2006.
78. Hedlund et al. "TH promoter driven selection strategies for purification of embryonic stem cell-derived DA neurons for transplantation to Parkinson's disease" abstract ISSCR 2006.
79. Chung et al. "A comparative study of ES cell-derived and ventral mesencephalon-derived neural precursors for their proliferation and differentiation potentials during mitogenic expansion" abstract, ISSCR 2006.
80. Pruszak et al. "Flow cytometric analysis and purification of neural and neuronal cell populations derived from human embryonic stem cells" abstract, ISAC XXIII Congress 2006.
81. Astradsson et al. "Update on cell type analysis of functional fetal dopamine cell suspension transplants in parkinson's disease" abstract, Annual Congress of the Scandinavian Neurosurgical Society 2006.
82. Hong et al. "Functional analysis of different promoters in lentiviral vectors for transgene expression at different stages of in vitro differentiated human embryonic stem cells" abstract, SfN 2006.
83. Chung et al. "Elevated expression of G-substrate in A10 dopaminergic neurons may contribute to their decreased vulnerability in Parkinson's disease" abstract, SfN 2006.
84. Sonntag et al. "Isolating and enriching dopamine neuronal cells from ES cells using transcriptional activation of drug resistance genes or fluorescent markers" abstract, SfN 2006.
85. Brunlid et al. "Immature and neurally differentiated mouse ES cells do not express a functional Fas/FasL system" abstract, SfN 2006.
86. Cooper et al. "Combined intrastriatal infusion of transforming growth factor- and noggin promotes proliferation, migration and neuronal differentiation from the subventricular zone in a rat model of Parkinson's disease" abstract, SfN 2006.
87. Pruszak et al. "Requirements for cell sorting and cell type analysis of stem cell-derived neural cell suspensions for transplantation" abstract, NECTAR 2006.
88. Lin et al. "Axon growth regulation of fetal and ES-derived dopaminergic neurons by Netrin-1 and Slits" abstract, Congress of Federation of Asian-Oceanian Neurscience Societies 2006.

Contact Information or Udall Center Link:
Harvard University/McLean Hospital Udall Center website