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Review
. 2012 Feb;45(1):87-98.
doi: 10.1007/s12035-011-8219-8. Epub 2011 Dec 9.

Genetically engineered mesenchymal stem cells as a proposed therapeutic for Huntington's disease

Scott D Olson  1 , Kari Pollock, Amal Kambal, Whitney Cary, Gaela-Marie Mitchell, Jeremy Tempkin, Heather Stewart, Jeannine McGee, Gerhard Bauer, Hyun Sook Kim, Teresa Tempkin, Vicki Wheelock, Geralyn Annett, Gary Dunbar, Jan A Nolta
Affiliations
Review

Genetically engineered mesenchymal stem cells as a proposed therapeutic for Huntington's disease

Scott D Olson et al. Mol Neurobiol. 2012 Feb.

Abstract

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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Figures

Fig. 1
Fig. 1
MSC/BDNF in the brain of an immune deficient mouse. Human mesenchymal stem cells engineered to secrete brain-derived neurotrophic factor (BDNF) and a reporter gene (enhanced green fluorescent protein, or eGFP) were transplanted into the brain of immune-deficient mice using stereotactic injection. Tissues were harvested for assessment of human cell engraftment and biosafety at different timepoints. Shown is engraftment at 6 days post-injection
Fig. 2
Fig. 2
Schema of proposed human MSC therapy for neurodegenerative disease. Bone marrow is harvested from a normal, qualified donor. MSC are expanded and transduced with viral vectors in the good manufacturing practice facility using qualified reagents and well-established standard operating procedures. The transduced cells are expanded, tested extensively, and banked. Following FDA clearance of the phase 1 clinical trial, the qualified cells will be implanted near the affected portion of the brain in symptomatic HD patients. MSC will be thawed, tested, and infused under MRI guidance by an experienced Neurorestorative Therapy Team. Patients will then be followed by experienced clinicians in the movement disorders clinic for evaluation of potential neurorestorative effects: slowing of disease progression as measured by total functional capacity score and delay in volumetric MRI changes known to occur in HD. Potential clinical improvement in severity of movement disorders and cognitive impairment as measured by the Unified HD Rating Scale (UHDRS) and a battery of cognitive tests will be monitored
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