Parkinson's disease: Mechanisms and models

This work was supported by grants from the National Institutes of Health (R01 AG048814, B.A.B.; RO1 DA15043, B.A.B.; P50 NS38377, V.L.D. and T.M.D.) Christopher and Dana Reeve Foundation (B.A.B.), the Novartis Institute for Biomedical Research (B.A.B.), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (B.A.B.), the JPB Foundation (B.A.B., T.M.D.), the Cure Alzheimer’s Fund (B.A.B.), the Glenn Foundation (B.A.B.), the Esther B O’Keeffe Charitable Foundation (B.A.B.), the Maryland Stem Cell Research Fund (2013-MSCRFII-0105-00, V.L.D.; 2012-MSCRFII-0268-00, T.M.D.; 2013-MSCRFII-0105-00, T.M.D.; 2014-MSCRFF-0665, M.K.). S.A.L. was supported by a postdoctoral fellowship from the Australian National Health and Medical Research Council (GNT1052961), and the Glenn Foundation Glenn Award. L.E.C. was funded by a Merck Research Laboratories postdoctoral fellowship (administered by the Life Science Research Foundation). W.-S.C. was supported by a career transition grant from NEI (K99EY024690). C.J.B. was supported by a postdoctoral fellowship from Damon Runyon Cancer Research Foundation (DRG-2125-12). L.S. was supported by a postdoctoral fellowship from the German Research Foundation (DFG, SCHI 1330/1-1).

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Neurotoxic reactive astrocytes are induced by activated microglia

Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.

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Astrocytes: biology and pathology

Cell Death During Development of the Nervous System

Mechanisms underlying inflammation in neurodegeneration.

: Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons leading to skeletal muscle atrophy, paralysis, and the death of patients within 2 to 5 years of disease onset. Currently, ALS cannot be prevented and disease progression can be only minimally delayed. Many previous reports have shown that glial cell line-derived neurotrophic factor (GDNF) ameliorates certain aspects of the disease in a number of different animal models of ALS. Despite many encouraging results, a strategy aimed at delivering GDNF has yet to be used in a clinical trial for ALS. Recent research and phase I/II clinical trial successes using adeno-associated virus (AAV) as a therapeutic tool have led to a renewed interest in a gene therapy approach for various disorders of the nervous system. To date, no clinical trial for ALS has yet exploited a gene therapeutic strategy, which prompted us to investigate this approach for ALS. Here, we have chosen to use an AAV based gene therapy approach as a straightforward strategy to promote GDNF production in muscles. Hypothesis: Intramuscular AAV5-GDNF injection will ameliorate motor neuron function in the SOD1G93A rat model of ALS. Objectives: To perform crucial and extensive pre-clinical studies to enable an investigational new drug (IND) application with the Food and Drug Administration (FDA) for the approval to move the use of intramuscular GDNF delivery by AAV5 into humans affected by ALS. Findings: Using a combination of DOD, ALS Association and institutional funding we have investigated the potential of intramuscular AAV1, AAV5, AAV2/6 and AAV9 encoding GDNF as a therapeutic approach to ALS. In all cases intramuscularly administered AAV encoding GDNF did not have an overt beneficial effect on motor neuron function. Alternative treatment: We propose to pursue the project using an ex-vivo gene therapeutic approach based on the intramuscular transplantation of mesenchymal stem cells (MSC) secreting GDNF.

Muscle-Derived GDNF: A Gene Therapeutic Approach for Preserving Motor Neuron Function in ALS

A method of creating an isogenic multicellular blood-brain barrier model from iPSCs is disclosed.

Isogenic blood-brain barrier model

The present invention teaches apparatuses, systems and methods for performing a variety of medical procedures, including those involving introducing one or more substances into a subjects body. In some embodiments, the invention teaches an imaging system that includes an ionizing radiation source and a digital radiation detector that are coupled to opposing blades of a tissue retractor

Clive N. Svendsen

Papers

Muscle-Derived GDNF: A Gene Therapeutic Approach for Preserving Motor Neuron Function in ALS

Isogenic blood-brain barrier model

Tissue retractor systems and methods