Parkinson's Disease Program

Functions of the nigrostriatal dopaminergic synapse and the use of neurotransplantation in Parkinson's disease.
Tsui A, Isacson O. J. Neurol. May 5, 2011.
Udall Parkinson's Disease Research Center of Excellence, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
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Cell Therapy Ahead for Parkinson's Disease.
Isacson O. Science 326: 1060, 2009.
Udall Parkinson's Disease Research Center of Excellence, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
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No Evidence for Disease-like Processes in Fetal Transplants.
Hallett PJ, Cooper O, Isacson O. Proc. Natl. Acad. Sci. published on-line Sept. 2, 2009, 10.1073/pnas.0908169106.
Udall Parkinson's Disease Research Center of Excellence, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
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Lack of Functional Relevance of Isolated Cell Damage in Transplants of Parkinson’s Disease Patients.
Cooper O, Astradsson A, Hallett PJ, Robertson H, Mendez I, Isacson O. J Neurol. Aug 2009; 256 Suppl 3: 310- 6.
Udall Parkinson's Disease Research Center of Excellence, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
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Protein Misfolding and Axonal Protection in Neurodegenerative Diseases.
Inoue H, Kondo T, Lin L, Mi S, Isacson O, Takahashi R. (Eds: Ovadi J, Orosz F). Springer Science Publishers, New York, 97- 110, 2009.
Udall Parkinson's Disease Research Center of Excellence, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
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Axon Guidance and Synaptic Maintenance: Preclinical Markers for Neurodegenerative Disease and Therapeutics.
Lin L, Lesnick TG, Maraganore DM, Isacson O. Trends in Neurosciences 32: 142- 9, 2009.
Udall Parkinson's Disease Research Center of Excellence, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
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Future of Cell and Gene Therapies for Parkinson’s Disease.
Isacson O and Kordower JH. Annals of Neurol. 64: 5122- 38, 2008.
Udall Parkinson's Disease Research Center of Excellence, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
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Molecular and Cellular Determinants for Generating ES-Cell Derived Dopamine Neurons for Cell Therapy.
Pruszak J and Isacson O. (Eds: Pasterkamp RJ, Smidt MP, Burbach JPH) Landis Bioscience: Austin, 112- 123, 2008.
Udall Parkinson's Disease Research Center of Excellence, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.

Directed Differentiation of Human ES Cells Into Ectoderm: Dopaminergic Neurons.
Pruszak J and Isacson O. (Eds: Sullivan S, Cowan C, Eggan K) Wiley 2007; 337- 48.
Udall Parkinson's Disease Research Center of Excellence, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.

Histopathological and Clinical Criteria for Analyzing Transplanted Human Dopamine Cells in Parkinson’s Disease.
Isacson, O, Lange N, Cooper O and Sanchez-Pernaute R. (Eds: Olanow W, Brundin P) Springer Science Publishers, New York, 166- 83, 2006.
Udall Parkinson's Disease Research Center of Excellence, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.

Recent Advances in Cell-based Therapy for Parkinson Disease
Astradsson A, Cooper O, Vinuela A, Isacson O. Neurosurg Focus 2008
Udall Parkinson's Disease Research Center of Excellence, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
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In this review, the authors discuss recent advances in the field of cell therapy for Parkinson disease (PD). They compare and contrast recent clinical trials using fetal dopaminergic neurons. They attribute differences in cell preparation techniques, cell type specification, and immunosuppression as reasons for variable outcome and for some of the side effects observed in these clinical trials. To address ethical, practical, and technical issues related to the use of fetal cell sources, alternative sources of therapeutic dopaminergic neurons are being developed. The authors describe the progress in enrichment and purification strategies of stem cell-derived dopaminergic midbrain neurons. They conclude that recent advances in cell therapy for PD will create a viable long-term treatment option for synaptic repair for this debilitating disease.

Neural cells differentiated in vitro from human embryonic stem cells (hESC) exhibit broad cellular heterogeneity with respect to developmental stage and lineage specification. Here we describe standard conditions for the use and discovery of markers for analysis and cell selection of hESC undergoing neuronal differentiation. To generate better-defined cell populations, we established a working protocol for sorting heterogeneous hESC-derived neural cell populations by fluorescence activated cell sorting (FACS). Using genetically labeled synapsin-GFP+ hESC-derived neurons as a proof-of-principle we enriched viable differentiated neurons by FACS. Cell sorting methodology using surface markers was developed, and a comprehensive profiling of surface antigens was obtained for immature ES cell types (such as SSEA-3, -4, TRA-1-81, TRA-1-60), neural stem and precursor cells (such as CD133, SSEA-1 [CD15], A2B5, FORSE-1, CD29, CD146, p75 [CD271]) and differentiated neurons (such as CD24 or NCAM [CD56]). At later stages of neural differentiation, the neural cell adhesion molecule NCAM (CD56) was used to isolate hESC-derived neurons by FACS. Such FACS-sorted hESC-derived neurons survived in vivo after transplantation into rodent brain. These results and concepts provide (1) a feasible approach for experimental cell sorting of differentiated neurons, (2) an initial survey of surface antigens present during neural differentiation of hESC, and (3) a framework for developing cell selection strategies for neural cell-based therapies.

Toward full restoration of synaptic and terminal function of the dopaminergic system in Parkinson's disease by stem cells.
Isacson O, Bjorklund LM, Schumacher JM. Ann Neurol. 2003;53 Suppl 3:S135-46; discussion 146-8.
Udall Parkinson's Disease Research Center of Excellence, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
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New therapeutic nonpharmacological methodology in Parkinson's disease (PD) involves cell and synaptic renewal or replacement to restore function of neuronal systems, including the dopaminergic (DA) system. Using fetal DA cell therapy in PD patients and laboratory models, it has been demonstrated that functional motor deficits associated with parkinsonism can be reduced. Similar results have been observed in animal models with stem cell-derived DA neurons. Evidence obtained from transplanted PD patients further shows that the underlying disease process does not destroy transplanted fetal DA cells, although degeneration of the host nigrostriatal system continues. The optimal DA cell regeneration system would reconstitute a normal neuronal network capable of restoring feedback-controlled release of DA in the nigrostriatal system. The success of cell therapy for PD is limited by access to preparation and development of highly specialized dopaminergic neurons found in the A9 and A10 region of the substantia nigra pars compacta as well as the technical and surgical steps associated with the transplantation procedure. Recent laboratory work has focused on using stem cells as a starting point for deriving the optimal DA cells to restore the nigrostriatal system. Ultimately, understanding the cell biological principles necessary for generating functional DA neurons can provide many new avenues for better treatment of patients with PD.

PMID: 12666105 [PubMed - indexed for MEDLINE]

The production and use of cells as therapeutic agents in neurodegenerative diseases.
Isacson O. Lancet Neurol. 2003 Jul;2(7):417-24.
Department of Neurology and the Harvard Center for Neurodegeneration and Repair, Harvard Medical School, Boston, MA, USA.
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Although progressive neurodegenerative diseases have very different and highly specific causes, the dysfunction or loss of a vulnerable group of neurons is common to all these disorders and may allow the development of similar therapeutic approaches to the treatment of diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. When a disease is diagnosed, the first step is to instigate protective measures to prevent further degeneration. However, most patients are symptom-free until almost all of the vulnerable cells have become dysfunctional or have died. There are known molecular mechanisms and processes in stem cells and progenitor cells that may be of use in the future design and selection of cell-based replacement therapies for neurological diseases. This review provides examples of conceptual and clinical problems that have been encountered in the development of cell-based treatments, and specific criteria for the effective use of cells in the future treatment of neurodegenerative diseases.

PMID: 12849120 [PubMed - in process]

Huntington's Disease Program

What are the long-term effects of neural grafting in patients with Huntington's disease?
Isacson O. Nature Clinical Practice Neurology Accepted 12 June 2006
Neuroregeneration Laboratories, Departments of Neurology and Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA isacson@hms.harvard.edu
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Detailed genetic information is available for several neurological diseases characterized by regional neuronal loss, including Huntington's disease, but these genetic findings have not yet produced new treatments for patients, although they have improved the diagnosis.1, 2 In Huntington's disease, there is a genetically predetermined process causing death of neurons within the patient's caudate­putamen (striatum). Transplanted neural tissue (neurons and glia progenitors) lacking the mutated gene can replace the disease-prone neurons and create new functional connections. Such cell transfer can also potentially slow down neurotoxic processes by the release of neurotrophic factors from the transplanted cells.3 In the future, neural replacement could perhaps be combined with other factors that promote regeneration and recovery of function.

Generalized brain and skin proteasome inhibition in Huntington's disease.
Seo H, Sonntag KC, Isacson O. Ann Neurol 2004 Published Online: 23 Jul 2004
Neuroregeneration Laboratories, Departments of Neurology and Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA isacson@hms.harvard.edu
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Mutated intracellular huntingtin is widely expressed in tissues of Huntington's disease (HD) patients. Intraneuronal nuclear protein aggregates of mutant huntingtin are present in HD brains, suggesting a dysfunction of the ubiquitin proteasome system (UPS). Because many cells and tissues can cope with the abnormal gene effects while others dysfunction and die, we determined gene-induced effects and considered the hypothesis that the gene causes multiple intracellular problems, but severe pathology is seen only in selected brain regions. In this study, we found inhibition of UPS function in both early (0-1, with no or little neuronal loss) and late (3-4, with more severe neuronal loss) stage HD patients' cerebellum, cortex, substantia nigra and caudate-putamen brain regions. Late HD stage increases in ubiquitin levels were unique to caudate-putamen. HD patients' skin fibroblasts also had UPS inhibition similar to brain despite increases in proteasome -subunit expression. Gene delivery and expression of proteasome activator PA28 increased UPS function in normal but not HD fibroblasts. These generalized UPS problems are associated with severe neuronal pathology only when coupled with decreases in brain-derived neurotrophic factor levels, mitochondrial complex II/III activity, and increases of ubiquitin levels particularly as seen in the caudate-putamen of HD patients.

Alzheimer's, ALS and Other Neurodegenerative Diseases

ALS model glia can mediate toxicity to motor neurons derived from human embryonic stem cells.
Hedlund E and Isacson O. Cell Stem Cell, 3: 575- 6, 2008.
Neuroregeneration Laboratory, McLean Hospital, Program in Neuroscience and Dept of Neurology, Harvard Medical School, Belmont, MA 02478-9106, USA.
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Cell therapy and stem cells in animal models of motor neuron disorders.
Hedlund E, Hefferan M, Marsala M, Isacson O. European Journal of Neuroscience, Vol. 26, pp. 1721 - 37, 2007.
Neuroregeneration Laboratory, McLean Hospital, Program in Neuroscience and Dept of Neurology, Harvard Medical School, Belmont, MA 02478-9106, USA. isacson@helix.mgh.harvard.edu
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Amyotrophic lateral sclerosis (ALS), spinal bulbar muscular atrophy (or Kennedy's disease), spinal muscular atrophy and spinal muscular atrophy with respiratory distress 1 are neurodegenerative disorders mainly affecting motor neurons and which currently lack effective therapies. Recent studies in animal models as well as primary and embryonic stem cell models of ALS, utilizing over-expression of mutated forms of Cu/Zn superoxide dismutase 1, have shown that motor neuron degeneration in these models is in part a non cell-autonomous event and that by providing genetically non-compromised supporting cells such as microglia or growth factor-excreting cells, onset can be delayed and survival increased. Using models of acute motor neuron injury it has been shown that embryonic stem cell-derived motor neurons implanted into the spinal cord can innervate muscle targets and improve functional recovery. Thus, a rationale exists for the development of cell therapies in motor neuron diseases aimed at either protecting and/or replacing lost motor neurons, interneurons as well as non-neuronal cells. This review evaluates approaches used in animal models of motor neuron disorders and their therapeutic relevance.

Alzheimer's disease and Down's syndrome: roles of APP, trophic factors and ACh.
Isacson O, Seo H, Lin L, Albeck D, Granholm AC. Trends Neurosci. 2002 Feb;25(2):79-84.
Neuroregeneration Laboratory, McLean Hospital, Program in Neuroscience and Dept of Neurology, Harvard Medical School, Belmont, MA 02478-9106, USA. isacson@helix.mgh.harvard.edu
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Recent therapeutic investigations of Alzheimer's disease (AD) have been guided by two seemingly opposed hypotheses: the amyloid cascade theory, which favors the amyloid plaques as the cause of AD; and the cholinergic theory, which favors cholinergic neuron loss as the cause. New investigations indicate that the synthesis and processing of the amyloid precursor protein (APP) is linked to the trophic actions of nerve growth factor. A pathological cascade in both AD- and Down's syndrome-related memory loss could be triggered by alterations in APP processing or ACh-mediated neuronal function, or both, which in turn trigger the overexpression of amyloid beta, synaptic malfunction and trophic factor loss in target regions. This eventually leads to synaptic and dendritic loss with age.
Publication Types:
* Review
* Review, TutorialPMID: 11814559 [PubMed - indexed for MEDLINE]