The Morris K. Udall Center for Excellence in Parkinson’s Research at Harvard University/McLean Hospital

Director: Ole Isacson, M.D.

Title: Novel Therapeutic Approaches for Parkinson’s Disease

Website: http://www.neuroregeneration.org/

 

Central Theme and Center Structure

The scientific approaches for the Harvard/McLean Udall Center focus on the most urgent development of new methods for medical applications. The discovery of the cellular changes that precede functional loss is modeled and explored in Project 1 (Ole Isacson). Specific models of degeneration also provide clues to new biomarkers and treatments in Project 1. Biomarkers are generated to successfully test neuroprotection therapies in future PD patients. Project 2 (Roger Spealman) has established new paradigms based on blood and imaging markers (Core B; Anna-Liisa Brownell) in collaboration with Clinical Core C (Ole Isacson). To create novel therapies that are not dependent on diffuse (systemic) drug delivery, Projects 2 and 3 (Kwang-Soo Kim) approach new findings on connectivity. Our explorations point to synaptic and axonal compartments of the cell as new “fields” of new treatment approaches (Projects 2 and 3). Several of these projects utilize novel stem cell technology (including PD patient-specific iPS cells) to make new observations and pre-clinical contributions to PD research.

In summary, the Morris K. Udall Center of Excellence at Harvard Medical School/McLean Hospital focuses on providing PD research that moves the neuroprotection and cell regeneration field forward in a goal-oriented manner. We have a broad menu of techniques and specialties for carrying out collaborative experiments on PD. For instance, the genomic analysis for DA regional markers started out in Project 1 of the Center (PI: Dr. Isacson), connected with Project 3 (PI: Dr. Kim).  These results and focused collaborations with a genomics component provided us with laser capture analysis of specific cells vulnerable to PD in the substantia nigra (see Project 1 and Core C).  This led to collaboration with the University of Miami Udall Center (PI: Vance) and Mayo Rochester (Udall Mayo Jacksonville) with Dr. Jim Maraganore.  In addition, this has enabled interactions with the Brigham & Women’s Hospital genomics group (Scherzer) and PD pathology core groups now providing a microchip analysis of normal and parkinsonian brains focusing on cells that are affected in idiopathic disease (in Clinical Core C, including data sets provided to Udall PD neuropathological database/Mayo Clinic Udall Center).  This has also led to new collaborative work (on linkage-analysis and genomics) on studying our A9/A10 genomics hits on axonal guidance pathway molecules, Dr. Jim Maraganore at Mayo Rochester (affiliated with Udall Center, Mayo Jacksonville). Our shared data has led to an accelerated pace of discovery and scope in GWAS and genomic convergence for candidate genes and bioinformatics analyses. We have also sharpened analytic tools for choosing candidate molecules that enter experimental models of neuroprotection and vulnerability, relevant to the discovery of PD treatments (Project 1).

A very specific expertise of this Harvard University/McLean Hospital Udall PD Center is stem cell technology.  The original Center grant award generated work on the first functional rodent embryonic stem (ES)-cell derived dopaminergic neurons in transplantation. This very productive work has led to collaborations and sharing of data across the country.  In particular, this project led to a primate and human stem cell study in collaboration with Memorial Sloan Kettering of New York, where Dr. Lorenz Studer, in close collaboration with us, initially provided stem cells for primate cell transplantation.  These cells are first grown by various protocols in cell culture, which have been developed over the last 4 years. Transplantation of post-mitotic immature midbrain-like DA neurons derived from primate ES or iPS cells has been performed into the MPTP primate model of PD (Project 2 and Core C). The direct program-like synergy between Projects 1, 2 and 3 is also evident in the stem cell and cell culture work.  For example, the former Project 3-based and current Core C stem cell work has led to new and innovative stem cell protocols for primates in Project 2. Dr. Ivar Mendez, who is a clinical collaborator of Core C, is a Canadian clinician-scientist with outstanding neurosurgical training and expertise, is currently working with patients in clinical transplantation trials. Dr. Mendez is planning to use the parallel FACS and DA marker technology developed by Core C for enhancement of their clinical protocols. The stem cell work has thus progressed to a new level, where we can envision the required steps to a future human clinical trial. 

The technology and scientific expertise at the Harvard University/McLean Udall PD Center also involves functional studies of potentially therapeutic drugs and cells in animals.  The animal models available provide both correlative and transgenic systems for testing neuroprotection, or cell and gene transfer.  The gene transfer methodology and expertise in the Center provides synergism and sharing of technology across projects.  The wide expertise in gene transfer and gene constructs allows the investigators to move from gene discovery in Project 1 (and collaborations) to constructing gene and viral vectors that can be used both to produce models (i.e. improving understanding of the pathological sequence in PD), as well as gene therapy in Project 2 (providing gene expression that would slow down progression of the disease).  This work is a spin-off of the existing Center projects (for example, new restorative paradigms in Project 3 can be applied in Project 2), and has generated a number of new projects among collaborative labs across the country.

In this way, the Center is providing a unique environment for building and enhancing scientific work centered around novel treatments for PD, that have not yet reached the clinic in a final form.

 

Available Resources

(coming soon)

 

Recent Significant Advances

• Seven cell endogenous novel molecular candidates were identified by cell-type specific molecular profiling (from 45 candidates with > 3-fold gene expression differences) potentially explaining neuroprotective differences observed between vulnerable A9 vs. resilient A10 neurons to all known etiologies of Parkinson’s disease.
• By using normal gene expression from vulnerable versus relatively protected rodent and human dopamine (DA) candidates were tested by gain or loss of function experiments using in vitro through in vivo studies.
• G-substrate and RAB3B were demonstrated to be more expressed in dopaminergic terminals projected from the VTA (A10) compared to the SN (A9) in human brain. Overexpressing G-substrate or RAB3B protected A9 DA neurons from 6-OHDA mediated toxicity in vitro and in vivo.
• Lingo-1 antibodies proved to be effective against several PD mimetic toxic processes (Inoue et al. 2007).
• Neuroinflammation was demonstrated as a major factor in creating PD-like degeneration in several animal models, and IL1B receptor antagonists to be protective against LPS induced toxicity (Koprich et al. 2008).
• PET imaging of dopamine transporters using carbon-11 labeled 2β-carbomethoxy-3 β -(4-fluorophenyl)tropane demonstrated improved dopaminergic function after embryonic stem cell transplantation of dopaminergic neurons differentiated from embryonic stem cells.
• Functional MR imaging was used to study recovery of dopaminergic system after transplantation and gene therapy, based on studies of dopamine release.
• The successful engraftment of primate parthenogenetic ES cell derived DA cells was accomplished in rodent and primate models of PD (Sanchez-Pernaute et al. 2008).
• Midbrain-like DA neurons could be purified using the Pitx3 knock-in mouse ES cells and its transplantation can ameliorate motor impairments in animal models of PD (Hedlund et al. 2008).
• Novel cell sorting technology was developed and adapted for elimination of tumor forming hES cells, and enrichment of DA neurons that are needed for PD transplantation.
• Advanced clinical collaborative work illustrated that the prototype for fetal cell transplantation in Parkinson’s disease can be highly effective in Parkinson’s disease patients (Mendez et al. 2005).
• Human fetal dopamine neurons transplanted into the brains of patients with severe Parkinson’s disease can survive for at least 14 years without being significantly affected by the ongoing disease process of the host brain (Mendez et al. 2008).
• First miPS cell differentiation into functional DA neurons; and use in animal models of PD (Wernig et al. 2008).
• Human iPS cell development of PD patient specific iPS cell lines with DA neuron differentiation capacity (resource shared with other Udall Centers) (Soldner et al. 2009).

 

Selected Recent Publications

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. 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 2007;104:14430-5.

KoprichJB, Reske-NielsenC, MithalP, 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.

Hedlund EM, Pruszak J, Lardaro T, Ludwig W, Viñuela A, Kim KS, Isacson O. 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 2008;26:1526-36.

Wernig M, Zhao J-P, Pruszak J, HedlundE, FuD, SoldnerF, Constantine-Paton M, IsacsonO, Jaenisch R. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s. Proc Natl Acad Sci USA 2008;105:5856-61.

Mendez I, Vinuela A, Astradsson A, Mukhida K, Hallett P, Robertson H, Tierney T, Holness R, Dagher A, Trojanowski JQ, Isacson O. Dopamine neurons implanted into people with Parkinson’s disease survive without pathology for 14 years. Nat Med 2008;14:507-9.

Sanchez-Pernaute R, Lee H, Patterson M, Reske-Nielsen C, Yoshizaki T, Sonntaq KC, Studer L, Isacson O. Parthenogenetic dopamine neurons from primate embryonic stem cells restore function in experimental Parkinson’s disease. Brain 2008;131(Pt 8):2127-39.

Lin L, Lesnick TG, Maraganore DM, Isacson O. (2008) Axon guidance and synaptic maintenance: preclinical markers for neurodegenerative disease and therapeutics. Trends in Neurosciences 2009;32:142-9.

Soldner F, Hockemeyer D, Beard C, Gao Q, Bell GW, Cook EG, Hargus G, Blak A, Cooper O, Mitalipova M, Isacson O, Jaenisch R. Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 2009;136:964-77.

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

 

Public Health Statement

This Research Center has a broad expertise, but focuses on the basic and translational research that can lead to novel pilot clinical trials and therapeutic innovations for PD. The concerted effort created by the Harvard University/McLean Hospital Udall PD Center provides specialized work on CNS regeneration and repair. These investigators and collaborators have embraced PD problems from a scientific and a medical perspective. We believe this work will continue to lead to better treatments and insights about PD, in particular for focused research on gene pathways relevant to neuroprotection (not only neurodegenerative mechanisms, which is the more typical research) for PD, as well as novel restorative cell therapies.  In addition, it provides a Center of Excellence for education and training for both clinicians and scientists with an interest in PD.