Funding opportunities

Directed Stem Cell Recruitment into the CNS in Response to Coxsackievirus Infection

Funding Type: 
New Faculty II
Grant Number: 
RN2-00939
Funds requested: 
$1 788 000
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
Improved and more effective treatment strategies to alleviate the clinical symptoms associated with multiple sclerosis (MS) and Alzheimer's disease remain problematic. Stem cell-based therapy offers the great potential to improve neurological function by replacement of key neural cells in the central nervous system (CNS). A better understanding of targeted stem cell migration across the blood-cerebral spinal fluid (CSF)-barrier and subsequent differentiation into therapeutic cells may assist clinicians and researchers in maximizing the efficacy of stem cell based treatments. Furthermore, many previous studies utilizing stem cell-based therapy for tissue regeneration have relied on the seemingly inherent ability of stem cells to migrate and differentiate somewhat haphazardly into predetermined areas in damaged tissues. However, the random inoculation and migration of stem cells, regardless of regenerative potential, is unlikely to lead to the most efficient recruitment of stem cells and subsequent repair of critically damaged regions. Utilizing our neurotropic viral infection model which appears to induce the recruitment of peripheral stem cells, we will characterize the peripheral stem cells responsible for stem cell migration across the blood-CSF-barrier, and determine necessary recruitment factors upregulated during infection. Additionally, we will test the advantages of utilizing an attenuated or defective enterovirus as a novel viral vector for gene transfer into stem cells. The ability to insert foreign genes into stem cells may assist in proper stem cell differentiation, expression of therapeutic molecules, and protection of donor cells from the host immune response. Finally, we will evaluate the therapeutic use of transduced stem cells guided through the blood-CSF-barrier with novel chemoattractant molecules utilizing a relapsing-remitting mouse model of MS (EAE), and in a mouse model of Alzheimer's disease (hAPP751 transgenic mice) . MS is thought to be an autoimmune disease in which the loss of myelin contributes to CNS damage and clinical disease. Alzheimer's disease, a dementia affliction affecting over 20 million people worldwide, is a neurodegenerative disease with no known cure. Stem cell transplantation may be a therapeutic approach for the re-establishment of myelinated axonal fibers, replacement of damaged neurons and a return to proper neuronal function. The addition of regulatory genes into stem cells may help protect the newly differentiated cells from suffering from the same fate as their non-functioning neighbor cells. We hope that the proposed research will assist in the development of novel reagents for optimized stem cell-based therapy in patients suffering from neurological diseases.
Statement of Benefit to California: 
Approximately 400,000 Americans suffer from the neurological symptoms associated with multiple sclerosis (MS). Furthermore, over 5 million people in the US and Europe alone suffer from the dementia associated with Alzheimer's disease. The therapeutic use of stem cells may provide the basis for improving the lives of patients suffering from MS, Alzheimer's disease, and a variety of other neurological diseases. However, much remains to be understood regarding productive stem cell migration and proper differentiation of therapeutic neural cells in the host. Oligodendrocytes are essential cells in the central nervous system (CNS) that help to protect the axons of nerve fibers by producing a fatty tissue called myelin. In MS, myelin is lost in many region of the CNS thereby producing sclerotic lesions. Hence, the ability to promote new myelin formation in damage regions by the addition of new oligodendrocytes may be a potential therapy for the alleviated the effects of clinical disease. In contrast, Alzheimer's disease is associated with plaques and tangles in the CNS which can affect normal neuronal function and lead to memory loss, loss of major bodily functions , and eventual death. The replacement of damaged neurons and the reduction or reversal of plaques and tangles may be considered a possible treatment to ameliorate the symptoms associated with Alzheimer's disease. The project will provide new insights on how stem cells may traverse through the blood-cerebral spinal fluid-barrier and differentiate into the various cell types found within the CNS. Furthermore, we will test the ability of using a well characterized enterovirus that efficiently infects stem cells, as a viral gene delivery system. Our hope is that the information gained from our efforts will point to new directions, whereby optimized stem cell-based therapy may be of great benefit to those suffering from MS, Alzheimer's disease, and other neurological disabilities.
Review Summary: 
This applicant proposes to investigate the mechanisms of coxsackievirus-induced recruitment and transdifferentiation of neural-like stem cells from the periphery into the central nervous system (CNS). The project is based on the observations that the virus preferentially infects neural stem cells and recruits neural-like stem cells from the periphery into the CNS in response to injury from infection. Three aims are proposed: 1) a search for peripheral stem cell populations that respond to virus infection in the CNS, 2) the identification of chemoattractant molecules that are responsible for the suspected stem cell recruitment into the CNS following infection, and 3) developing vectors based on this virus and testing of the possible ability of stem cells transduced with this viral vector expressing regulatory genes to ameliorate disease in transgenic mouse models of multiple sclerosis (MS) and Alzheimer’s disease (AD). This is a novel, well-written proposal by a new investigator. However, reviewers commented that the proposal is overly ambitious, consisting of more work than can be done thoroughly in the time proposed. They were also disturbed that the project is based on a limited amount of data that the virus preferentially infects neural stem cells during acute infection. Finally, although interesting information may emerge from the investigator’s preliminary findings, the reviewers considered the project high risk and viewed the therapeutic potential of a vector derived from this virus as relatively low. The research plan is extremely detailed and involved. Reviewers commented that elucidating the mechanism of virus action might indirectly lead to the development of improved methods for targeted genetic manipulation of neural stem cells and/or improved control of stem cell migration/homing. However, it was not clear to reviewers that new chemoattractants would be discovered using the proposed techniques nor that the proposed follow-up experiments would be sufficient to characterize the effect of a putative chemoattractant, making this a high risk aim. The strongest aim is the final one, in which the applicant proposes to explore the action of specific regulatory genes on disease models (MS and AD). This aim was considered interesting and commendable, although the likelihood that results would lead to an improvement in disease progression was considered to be low. The investigator has experience with the virus, but reviewers were concerned by his/her lack of experience with stem cells and neurons. The mentoring plan includes monthly meetings with faculty who are appropriate mentors given their expertise, and was considered adequate. On the other hand, an extensive career development plan is not specifically outlined. Reviewers commented that important milestones and goals for career development were not described. The applicant’s institution has made a commitment to stem cell research, and to this investigator. The department chair has provided a very strong letter of support. However, reviewers commented that the amount of time allocated for research is not specifically stated, and were concerned that teaching responsibilities might still remain too high to allow the applicant enough time to complete the ambitious research project proposed.
Conflicts: 

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