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  Director: Prof. Ole Isacson
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Prof. Ole Isacson: Biography and work at the Neuroregeneration Research Institute

Dr. Ole Isacson is Professor of Neurology (Neuroscience) at Harvard Medical School. He is the Director of the Center for Neuroregeneration Research/ Neuroregeneration Laboratories at McLean Hospital, and an NIH Udall Parkinson's Disease Research Center of Excellence grant awardee. Dr. Isacson is also a member of the Scientific Advisory Board of the Harvard NeuroDiscovery Center and Principal Faculty of Harvard Stem Cell Institute. He received his Medical Bachelor (1984) and Doctor of Medicine (a research doctoral degree in Medical Neurobiology, 1987) from the University of Lund in Sweden. In 1989, after a 2 year postdoctoral fellowship position at Cambridge University, England, Dr. Isacson was recruited to Harvard as an Assistant Professor of Neuroscience and there established an independent research laboratory for his work on neuroregeneration. Over the last two decades his original laboratory has grown to an internationally recognized academic research center for Parkinson's disease and related disorders, funded by the NIH, DOD and private foundations. Toward the end of 2010 the Center for Neuroregeneration Research was designated an Institute by McLean Hospital. Dr. Isacson's scientific models and studies of conceptually new therapies for neurodegenerative diseases have resulted in many new findings and clinical trials for Parkinson's and Huntington's disease. He is Editor-In-Chief of Molecular and Cellular Neuroscience and past Receiving Editor of the European Journal of Neuroscience (2002-2008) and on the board of numerous scientific journals. He is a founding member and past President of the American Society for Neural Transplantation and Repair, and the past President of the international Cell Transplant Society, CTS (branch of The Transplantation Society, TTS). He serves as a scientific reviewer and advisor to the NIH, DOD and many Parkinson community groups. Dr. Isacson has received several international prizes, research awards and lectureships. He was elected Fellow of the American Association for the Advancement of Science (AAAS) in 2014. He is author or co-author of over 300 scientific research publications in neuroscience and neurology, and 3 books in his field.

Prof. Isacson's research center has had an impact on several neurodegenerative disease problems. In the early 1990s his laboratory showed in Parkinson's and Huntington's disease model studies, that the specific neurons most vulnerable to the diseases could be protected from toxic processes, including lesions and energetic metabolic failures (Schumacher et al. 1991, Frim et al. 1994). Work also showed that degenerated neurons in the striatum could be replaced by implanted fetal GABAergic neurons, with restorative functional effects (Hantraye et al. 1992). Such implanted cells could also grow in Huntington patients in an appropriate way (Freeman et al. 2000). While exploring new donor cell sources for therapy, Dr. Isacson's lab was the first to transplant embryonic stem (ES) cells differentiated in cell culture into gamma-aminobutyric acid (GABA) expressing neurons in animal models in 1995 (Dinsmore et al. 1996). Dr. Isacson's lab was also the first to demonstrate that normal midbrain dopaminergic neurons could develop from uninduced ES cells in 1998 (Deacon et al 1998). This work led to the first demonstration that ES cells could provide functional dopamine neurons to animal models of Parkinson's by Dr. Isacson's research group in 2002 (L.M. Bjorklund et al. 2002). In depth fundamental scientific discovery work in his lab also revealed that many damaged neuronal networks could be anatomically reconnected by fetal or stem cell derived neurons precisely in the patterns seen in developing brains, even when donor cells were from different donor species (Isacson et al. 1995, Isacson and Deacon, 1996, 1997). The specificity of such microscopic reconnections showed that the adult brain retains most of the necessary information to make new synapses and restore brain circuitry (Isacson et al. 1995, Isacson and Deacon, 1996, 1997). For therapeutic applications, this was demonstrated both in animal models and later in the clinic for individual Parkinson patients that in principle, implanted individual neurons could reconstitute the dopamine system long-term (Isacson et al. 1995, Deacon et al. 1997, Mendez et al. 2005, 2008, Cooper et al. 2009, Tsui and Isacson 2012). These experiments demonstrated that functional repair is possible using cell therapies, either for trophic preservation or by restituting the neurotransmission. Scientists at the Center for Neuroregeneration Research have also shown that ES and iPS cells can generate the specific dopamine neurons (A9 and A10) that are involved in the degeneration that creates the syndrome of Parkinson's disease (S. Chung et al. 2002, 2005, Cooper et al 2010, 2012a). Innovative axon and synapse regeneration approaches are the focus of experiments in his laboratory. New discoveries demonstrate that ES or induced proliferative stem (iPS) cell derived neurons, including human cells, can reverse deficits in animal models and create functional neurotransmission in the brain's motor circuitry (L.M. Bjorklund et al. 2002, Hedlund et al. 2008, Wernig et al. 2008, Soldner et al. 2009, Hargus et al. 2010, Cooper et al 2010 , Hallett et al. 2013). To achieve practical goals in regenerative medicine for patients with neurological diseases, Dr Isacson's team has also developed novel neural cell sorting methods (Pruszak et al. 2007), genetic engineering and gene therapy (Seo et al. 2007, C.Y. Chung et al. 2007, Hemming et al. 2007, C.Y. Chung et al. 2009, 2010). In the analysis of how certain brain cell populations are vulnerable or resistant to neurodegenerative diseases, Dr. Isacson's group discovered specific molecular profiles of neurons, including iPSC-derived neurons obtained from patients or at-risk cases, that characterize vulnerable cell types. Such experiments provided information for new leads for neuroprotective therapeutics for Parkinson's, Huntington's diseases and Amyotrophic Lateral Sclerosis (ALS) (C.Y. Chung et al. 2005, 2007, 2009, 2010; Hedlund et al. 2007, 2010, McLean et al. 2011, Hallett et al. 2012, Cooper et al. 2012b, Sanders et al. 2014). Current studies in his laboratory also concentrate on interactions between brain tissue repair, degeneration and immune responses to provide neurobiological insights and new agents for future therapies (Koprich et al. 2008, C.Y. Chung et al. 2009, Deleidi et al. 2010, 2012, Hallett et al. 2012). Important scientific discoveries for neurological and psychiatric diseases made in the Center for Neuroregeneration Research show how brain cell circuitry and synapses previously degenerated can be restored or replaced (Lin et al. 2006, Inoue et al. 2007, Hedlund et al, 2008, Wernig et al 2008, Mendez, Vinuela et al 2008, Cooper et al. 2009, Hargus et al. 2010, Tsui and Isacson 2012). These scientific accomplishments provide novel technology and biological insights beyond currently available drug therapies for neurological and neurodegenerative diseases.


Selected Publications from Professor Isacson’s laboratory:

Cell therapy science and medicine for neurodegenerative diseases

Hantraye, P., Riche, D., Maziere, M. and Isacson, O. (1992) Intrastriatal grafting of cross-species fetal striatal cells reduces abnormal movements in a primate model of Huntington's disease. Proc. Natl. Acad. Sci. USA 89, 4187-4191.

Isacson, O., Deacon, T.W., Pakzaban, P., Galpern, W.R., Dinsmore, J., and Burns, L.H. (1995) Transplanted xenogeneic neural cells in neurodegenerative disease models exhibit remarkable axonal target specificity and distinct growth patterns of glial and axonal fibres. Nature Med. 1, 1189-1194.

Isacson, O. and Deacon, T.W. (1996) Specific axon guidance factors persist in the adult rat brain as demonstrated by pig neuroblasts transplanted to the rat. Neuroscience 75, 827-837.

Deacon, T., Schumacher, J., Dinsmore, J., Thomas, C., Palmer, P., Kott, S., Edge, A., Penney, D., Kassissieh, S., Dempsey, P. and Isacson, O. (1997) Histological evidence of fetal pig neural cell survival after transplantation into a patient with Parkinson's disease. Nature Med. 3, 350-353.

Freeman, T.B., Cicchetti, F., Hauser, R.A., Deacon, T.W., Li, X. C., Hersch, S.M., Nauert, G.M., Sanberg, P.R., Kordower, J.H., Saporta, S., Isacson, O. (2000) Transplanted fetal striatum in Huntington's disease: Phenotypic development and lack of pathology. Proc. Natl. Acad. Sci. USA 97, 13877-13882.

Mendez, I., Sanchez-Pernaute, R., Cooper, O., Vinuela, A., Ferrari, D., Bjorklund, L., Dagher, A., Isacson, O. (2005) Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson's disease. Brain 128, 1498-510.

Hedlund E, Hefferan MP, Marsala M, Isacson O. (2007) Cell therapy and stem cells in animal models of motor neuron disorders. Eur. J. Neurosci. 26; 1721-1737.

Hedlund EM, Pruszak J, Lardaro T, Ludwig W, Viñuela A, Kim KS, Isacson O. (2008) Embryonic Stem (ES) Cell-derived Pitx3-eGFP Midbrain Dopamine Neurons Survive Enrichment by FACS and Function in an Animal Model of Parkinson's Disease. Stem Cells 26:1526-36.

Mendez I, Vinuela A, Astradsson A, Mukhida K, Hallett P, Robertson H, Tierney T, Holness R, Dagher A, Trojanowski JQ, Isacson O. (2008) Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years. Nature Med. 14, 507-509.

Vinuela A, Hallett PJ, Reske-Nielsen C, Sotnikova TD, Caron MG, Gainetdinov RR, Isacson O. (2008) Implanted reuptake-deficient or wild-type DA neurons improve ON L-dopa dyskinesias without OFF-dyskinesias in a rat model of Parkinson's disease. Brain 131:3361-79.

Cooper O, Astradsson A, Hallett P, Robertson H, Mendez I, Isacson O. (2009) Lack of functional relevance of isolated cell damage in transplants of Parkinson's disease patients. J. Neurol. 256 (Suppl 3):S310-S316.

Hargus G, Cooper O, Deleidi M, Levy A, Lee K, Marlow E, Yow A, Soldner F, Hockemeyer D, Hallett PJ, Osborn T, Jaenisch R, Isacson O. (2010) Differentiated Parkinson patient-derived iPS cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats. Proc Natl Acad Sci USA 107:15921-6.

Tsui A and Isacson O. (2011) Functions of the Nigrostriatal Dopaminergic Synapse and the Use of Neurotransplantation in Parkinson’s Disease. J. Neurol. 258:1393-405.

Cooper O, Hallett P, Isacson O. (2012a) Using stem cells and iPS cells to discover new treatments for Parkinson's disease. Parkinsonism Relat Disord. Jan;18 Suppl 1:S14-6.

Lindvall O, Barker R, Brustle O, Isacson O and Svendsen C. (2012) Clinical Translation of Stem Cells in Neurodegenerative Disorders. Cell Stem Cell 10:151-5.

Neuroprotection and tissue regeneration
Schumacher, J.M., Short, M.P., Hyman, B.T., Breakefield, X.O., and Isacson, O. (l991). Intracerebral Implantation of Nerve Growth Factor-Producing Fibroblasts Protects Striatum Against Neurotoxic Levels of Excitatory Amino Acids. Neuroscience 45, 561-570.

Frim, D.M., Uhler, T.A., Galpern, W., Beal, M.F., Breakefield, X.O. and Isacson, O. (1994) Implanted fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevent 1-methyl-4-phenylpyridinium toxicity to dopaminergic neurons in the rat. Proc. Natl. Acad. Sci. USA 91, 5104-08.

Chung, C.Y., Seo, H., Sonntag, K-C. Brooks, A., Lin, L. and Isacson, O. (2005) Cell type specific gene expression of midbrain dopaminergic neurons reveals molecules involved in their vulnerability and protection. Hum. Mol. Genet. 14, 1709-25.

Chung C-Y, Koprich JB, Endo S, Isacson O. (2007) An endogenous serine/threonine protein phosphatase inhibitor, G-substrate, reduced vulnerability in models of Parkinson's disease. J. Neurosci. 27, 8314-23.

Hemming ML, Patterson M, Reske-Nielsen C, Lin L, Isacson O, Selkoe D. (2007) Reducing amyloid plaque burden via ex vivo gene delivery of an AB-degrading protease: a novel therapeutic approach to Alzheimer's disease. PloS Med, Aug 28:4(8):e262.

Inoue H, Lin L, Lee X, Shao Z, Mendes S, Snodgrass-Belt P, Sweigard H, Engber T, Pepinsky B, Yang L, Beal MF, Mi S, Isacson O. (2007) Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, structure, and function of dopaminergic neurons in Parkinson's disease models. Proc. Natl. Acad. Sci. USA 104, 14430-35.

Seo H, Sonntag K-C, Kim W, Cattaneo E, Isacson O (2007) Proteasome activator enhances survival of Huntington's disease neuronal model cells. Published Feb. 28, 2007. PLoS ONE 2(2): e238. doi:10.1371/journal.pone.0000238.

Koprich JB, Reske-Nielsen C, Mithal P, Isacson O. Neuroinflammation mediated by IL-1beta increases susceptibility of dopamine neurons to degeneration in an animal model of Parkinson's disease. J. Neuroinflamm. 2008,5:8. Doi:10..1186/1742-2094-5-8.

Chung C-Y, Koprich JB, Siddiqi H, Isacson O. (2009) Dynamic changes in axonal transport and presynaptic proteins with striatal neuroinflammation precede dopaminergic neuronal loss in a rat model of AAV-synucleinopathy. J Neurosci.;29(11):3365-73. NIHMSID: NIHMS103428.

Chung C-Y, Koprich JB, Hallett PJ, Isacson O. (2009) Functional enhancement and protection of dopaminergic terminals by RAB3B overexpression. Proc Natl Acad Sci USA 106:22474-79.

Chung C-Y, Licznerski P, Alavian KN, Simeone A, Lin Z, Martin E, Vance J, Isacson O. (2010) The transcription factor Otx2 determines axonal projections and vulnerability of midbrain dopaminergic neurons and carries age-dependent genetic risk for Parkinson's disease. Brain 133(Pt 7):2022-31.

Hedlund E, Karlsson M, Osborn T, Ludwig W, Isacson O. (2010) Global gene expression profiling of somatic motor neuron populations with different vulnerability identify molecules and pathways of degeneration and protection. Brain 133:2313-30. 

Deleidi M, Hallett PJ, Koprich JB, Chung C-Y, Isacson O. (2010) The Toll-Like Receptor-3 Agonist Polyinosinic:Polycytidylic Acid Triggers Nigrostriatal Dopaminergic Degeneration. J. Neurosci. 30:16091-101.

McLean JR, Hallett PJ, Cooper O, Stanley M, and Isacson O (2012) Transcript expression levels of full-length alpha-synuclein and its three alternatively spliced variants in Parkinson’s disease brain regions and in a transgenic mouse model of alpha-synuclein overexpression. Mol. Cell. Neurosci. 49:230-239.

Deleidi M and Isacson O (2012) Inflammatory and viral triggers of neurodegenerative disease. Science Transl Med. 4:121-3.

Hallett PJ, McLean JR, Kartunen A, Langston JW, and Isacson O. (2012) Alpha-synuclein overexpressing transgenic mice show internal organ pathology and autonomic deficits consistent with Parkinson’s disease. Neurobiol. Dis. 47:258–267.

Davies SE, Hallett PJ, Moens T, Smith G, Mangano E, Kim HT, Goldberg AL, Liu J-L, Isacson O, Tofaris GK. (2013) Enhanced ubiquitin-dependent degradation by Nedd4 protects against a-synuclein accumulation and toxicity in animal models of Parkinson's disease. Neurobiol. Dis., Dec 31, 2013  [Epub ahead of print].

Stem cell biology and therapeutic discovery
Dinsmore, J., Deacon, T., Ratliff, J., Pakzaban, P., Jacoby, D. and Isacson, O. (1996) Embryonic stem cells differentiated in vitro as a novel source of cells for transplantation. Cell Transplant. 5, 131-143.

Deacon, T., Dinsmore, J., Costantini, L.C., Ratliff, J. and Isacson, O. (1998) Blastula-stage stem cells can differentiate into dopaminergic and serotonergic neurons after transplantation. Exp. Neurol. 149, 28-41.

Bjorklund, L., Pernaute, R.S., Chung, S., Andersson, T., Chen, I.Y.C., McNaught, K.S.P., Brownell, A.-L., Jenkins, B.G., Wahlestedt, C., Kim, K.-S., Isacson, O. (2002) Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc. Natl. Acad. Sci. USA 99, 2344-2349.

Chung, S., Hwang, M., Kim, D.-W., Shin, B.-S., Hedlund, E., Hwang, D.Y., Kang, U.J., Isacson, O. and Kim, K.-S. (2005) The homeodomain transcription factor Pitx3 facilitates differentiation of mouse embryonic stem cells into AHD2-expressing dopaminergic neurons. Mol. Cell Neurosci. 28, 241-252.

Lin, L., and Isacson, O. (2006) Axonal growth of fetal and ES-derived dopaminergic neurons by Netrin-1 and slits. Stem Cells 24, 2504-13.

Pruszak J, Sonntag K-C, Aung MH, Sanchez-Pernaute R, Isacson O. (2007) Markers and methods for cell sorting of human embryonic stem cell-derived neural cell populations. Stem Cells 25:2257-68.

Hedlund EM, Pruszak J, Lardaro T, Ludwig W, Viñuela A, Kim KS, Isacson O. (2008) Embryonic Stem (ES) Cell-derived Pitx3-eGFP Midbrain Dopamine Neurons Survive Enrichment by FACS and Function in an Animal Model of Parkinson's Disease. Stem Cells 26, 1526-36

Wernig M, Zhao J-P, Pruszak J, Hedlund E, Fu D, Soldner F, Constantine-Paton M, Isacson O, Jaenisch R. (2008) Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's. Proc. Natl. Acad. Sci. USA 105, 5856-61.

Soldner F, Hockemeyer D, Beard C, Gao Q, Bell GW, Cook EG, Hargus G, Blak A, Cooper O, Mitalipova M, Isacson O, Jaenisch R. (2009) Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136, 964-977.

Hargus G, Cooper O, Deleidi M, Levy A, Lee K, Marlow E, Yow A, Soldner F, Hockemeyer D, Hallett PJ, Osborn T, Jaenisch R, Isacson O. (2010) Differentiated Parkinson patient-derived iPS cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats. Proc Natl Acad Sci USA 107:15921-6.

Cooper O, Hargus G, Deleidi M, Blak A, Osborn T, Marlow E, Lee K, Levy A, Perez-Torres E, Yow A, Isacson O. (2010). Differentiation of human ES and Parkinson's disease iPS cells into ventral midbrain dopaminergic neurons requires a high activity form of SHH, FGF8a and specific regionalization by retinoic acid. Molec. Cell. Neurosci. 45:258-66.

Deleidi M, Hargus G, Hallett PJ, Osborn T, Isacson O. (2011a) Development of histocompatible primate induced pluripotent stem cells. Stem Cells 29:1052-63.

Deleidi M, Cooper O, Hargus G, Levy A, Isacson O. (2011b) Oct4-induced Reprogramming is Required for Adult Brain Neural Stem Cell Differentiation into Midbrain Dopaminergic Neurons. PLoS One 6(5):e19926.

Cooper O, Hallett P, Isacson O. (2012a) Using stem cells and iPS cells to discover new treatments for Parkinson's disease. Parkinsonism Relat Disord. Jan;18 Suppl 1:S14-6.

Cooper O, Seo H, Andrabi S, Sundberg M, McLean J, Carrillo-Reid L, Xie Z, Osborn T, Hargus G, Deleidi M, Lawson T, Bogetofte-Thomasen H, Perez-Torres E, Clark L, Moskowitz C, Guardia-Laguarta C, Mazzulli J, Chen L, Volpicelli-Daley L, Romero N, Jiang H, Uitti RJ, Huang Z, Opala G, Feng J, Ross OA, Trojanowski JQ, Lee VM-Y, Krainc D, Marder K, Przedborski S, Surmeier DJ, Wszolek ZK, Dawson TM, Isacson O. (2012b) Pharmacological Rescue of Mitochondrial Deficits in iPSC-Derived Neural Cells from Patients with Familial Parkinson's Disease. Sci. Transl. Med. 4(141): 52-64.

Sanders, L.H., Laganiere, J., Cooper, O., Mak, S.K., Vu, B.J., Huang, Y.A., Paschon, D.E., Vangipuram, M., Sundararajan, R., Urnov, F.D., Langston, J.W., Gregory, P.D., Zhang, H.S., Greenamyre, J.T., Isacson, O., Schule, B. (2014) LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson’s disease patients: Reversal by gene correction. Neurobiol. Dis., Oct. 19, 2013 62:381-6.

Hallett P, Deleidi M, Astradsson A, Cooper O, Osborn T, Moore M, Perez-Torres E, Brownell A-L, Schumacher J, Spealman R, Isacson O. Long-term function and survival of Cynomolgus monkey iPS cell-derived dopamine neurons following autologous transplantation in a non-human primate model of Parkinson’s disease. Soc. Neurosci. Annual Meeting 2013, San Diego, CA

 

 

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