Genetically Engineered Mesenchymal Stem Cells as a Proposed Therapeutic for Huntington’s Disease

Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health Systems, 2921 Stockton Blvd., Room 1300, Sacramento, CA 95817, USA.
Molecular Neurobiology (Impact Factor: 5.14). 12/2011; 45(1):87-98. DOI: 10.1007/s12035-011-8219-8
Source: PubMed


There is much interest in the use of mesenchymal stem cells/marrow stromal cells (MSC) to treat neurodegenerative disorders, in particular those that are fatal and difficult to treat, such as Huntington's disease. MSC present a promising tool for cell therapy and are currently being tested in FDA-approved phase I-III clinical trials for many disorders. In preclinical studies of neurodegenerative disorders, MSC have demonstrated efficacy, when used as delivery vehicles for neural growth factors. A number of investigators have examined the potential benefits of innate MSC-secreted trophic support and augmented growth factors to support injured neurons. These include overexpression of brain-derived neurotrophic factor and glial-derived neurotrophic factor, using genetically engineered MSC as a vehicle to deliver the cytokines directly into the microenvironment. Proposed regenerative approaches to neurological diseases using MSC include cell therapies in which cells are delivered via intracerebral or intrathecal injection. Upon transplantation, MSC in the brain promote endogenous neuronal growth, encourage synaptic connection from damaged neurons, decrease apoptosis, reduce levels of free radicals, and regulate inflammation. These abilities are primarily modulated through paracrine actions. Clinical trials for MSC injection into the central nervous system to treat amyotrophic lateral sclerosis, traumatic brain injury, and stroke are currently ongoing. The current data in support of applying MSC-based cellular therapies to the treatment of Huntington's disease is discussed.

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    • "If exposure to young plasma proves sufficient to induce CNS rejuvenation in Alzheimer's patients (NCT02256306) as shown in aged mice (Villeda et al., 2014), one goal of future cell therapies may be to augment the supply of identified " youthful " factors required for CNS resilience against age-related stress. Active work is additionally ongoing to investigate cellular therapies for multiple sclerosis (Ferreira et al., 2015; Martino et al., 2010), Huntington's disease(Olson et al., 2012), traumatic brain injury (Richardson et al., 2010; Xiong et al., 2013) and epilepsy, (Roper and Steindler, 2013), and pediatric lysosomal storage diseases (Gupta et al., 2012; Selden et al., 2013), among others. Indeed, cell therapies may not be limited to CNS injuries or degeneration but are also under investigation to help combat brain tumors due to their migratory behavior, inherent anti-tumorgenic properties, and capacity to deliver genes, prodrugs or oncolytic viruses to sites of tumor infiltration (Bovenberg et al., 2013). "
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    ABSTRACT: Decisions about what experimental therapies are advanced to clinical trials are based almost exclusively on findings in preclinical animal studies. Over the past 30 years, animal models have forecast the success of hundreds of neuroprotective pharmacological therapies for stroke, Alzheimer׳s disease, spinal cord injury, traumatic brain injury and amyotrophic lateral sclerosis. Yet almost without exception, all have failed. Rapid advances in stem cell technologies have raised new hopes that these neurological diseases may one day be treatable. Still, how can neuroregenerative therapies be translated into clinical realities if available animal models are such poor surrogates of human disease? To address this question we discuss human and rodent neurogenesis, evaluate mechanisms of action for cellular therapies and describe progress in translating neuroregeneration to date. We conclude that not only are appropriate animal models critical to the development of safe and effective therapies, but that the multiple mechanisms of stem cell-mediated therapies may be particularly well suited to the mechanistically diverse nature of central nervous system diseases in mice and man. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Mar 2015 · European journal of pharmacology
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    • "It is possible to design siRNA targeted at the mutant allele in a selective way allowing a normal expression of wild type huntingtin[20]. Mesenchymal stromal cells have been develop to express siRNA and tested with success in a number of animal models and their potential to treat HD is promising [21]. A trial using a construct with siRNA in healthy volunteers inoculated with respiratory syncytial virus has demonstrated its antiviral activity, thus establishing a proof of concept for such an approach [22]. "
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    ABSTRACT: Research on the molecular mechanisms involved in Huntington's disease, a monogenic disorder with a complex phenotype including motor, behaviour, and cognitive impairments, is advancing at a rapid path. Knowledge on several of the multimodal pathways has now lead to the establishment of rational strategies to prepare trials of several compounds in affected people. Furthermore, improved understanding of the phenotype and on ways of assessing it, as well as the process of developing biomarkers, allows setting the frame for such studies. In this brief review, the present status of some of these aspects is examined.
    Full-text · Article · Jan 2013 · Translational Neurodegeneration
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    • "For instance, modification of a primary MSC population with small chemical compounds and subsequent screening for expression or secretome profiles could be considered to improve the study design and the efficacy (Ranganath et al., 2012). Genetic modification to express factor(s) that are expected to mediate or enhance the therapeutic effect and characterization of transfected clones also represents rational development (Olson et al., 2012). The comparison of subpopulations or primary cultures of different origin will increase the number of candidates for the screening and has been applied for the cell-based medicinal product development (Li et al., 2012). "
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    ABSTRACT: Advanced therapy medicinal products (ATMPs), including cell therapy products, form a new class of medicines in the European Union. Since the ATMPs are at the forefront of scientific innovation in medicine, specific regulatory framework has been developed for these medicines and implemented from 2009. The Committee for Advanced Therapies (CAT) has been established at the European Medicines Agency (EMA) for centralized classification, certification and evaluation procedures, and other ATMP-related tasks. Guidance documents, initiatives, and interaction platforms are available to make the new framework more accessible for small- and medium-sized enterprises, academia, hospitals, and foundations. Good understanding of the centralized and national components of the regulatory system is required to plan product development. It is in the best interests of the cell therapy developers to utilize the resources provided starting with the pre-clinical stage. Whilst there have been no mesenchymal stem cell (MSC)-based medicine authorizations in the EU, three MSC products have received marketing approval in other regions since 2011. The information provided on the regulatory requirements, procedures, and initiatives is aimed at facilitating MSC-based medicinal product development and authorization in the EU.
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