Funding opportunities

Tools to Enable Bone Marrow Stem Cell Derived Regenerative Medicine: Harvest, Processing & Delivery

Funding Type: 
Tools and Technologies I
Grant Number: 
RT1-01076
Funds requested: 
$849 870
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
Bone marrow (BM) is a rich source of adult stem cells including blood forming stem cells currently used in over 55,000 bone marrow transplants each year . Other bone marrow stem and progenitor cells have recently been found to be increasingly useful for a widening array of regenerative therapies. The objectives of this research is to further develop 3 novel enabling tools to address the unmet needs for a minimally invasive harvest of bone marrow, the rapid processing of marrow, and the targeted delivery of BM derived stem cells. BM transplantation has been used to treat patients with a wide variety of disorders. Preclinical studies and a rapid progression of clinical studies suggest that marrow-derived stem cells may be utilized to mediate repair and regeneration of a variety of damaged tissues including in orthopedics, for treatment of damaged cardiovascular systems, neural tissues, and for organ systems such as liver, kidney & pancreas. The effectiveness of any marrow stem cell therapy depends particularly on the numbers and function of harvested stem cells, as numbers generally correlate positively with clinical outcome. In addition the ease of obtaining marrow, reproducibility and quality of the marrow are critical for enabling use in the clinic and optimizing health benefits. HARVEST: Current procedures for harvesting BM are invasive, slow, painful and inefficient, and utilize a large bone marrow aspiration needle, which must repeatedly puncture the hip bone to serially harvest small BM volumes. This can require up to 200 separate puncture/aspirates, often under general anesthesia. Aspiration of >5ml per puncture results in marrow highly diluted with peripheral blood. We have developed a novel powered harvesting device, to address the need for an effective minimally invasive approach, under local anesthesia, via a single puncture. Animal studies found a 10X increase in stem cell yield/ml with the device compared to standard harvest needles, and initial clinical trials with the novel system demonstrated safety and efficacy. We propose to develop a 2nd Generation production level harvest system which can be utilized for bone marrow transplantation and to enable many current and future regenerative medicine trials and therapies. PROCESSING of harvested BM ito enrich for stem cells is critical for cell therapy but labor and time intensive. A new sound based cell separation technology shows promise as a rapid approach to isolate cells from blood. We will further develop this technology for use with marrow. DELIVERY: Effective stem cell therapy requires targeted cell delivery. Tools to deliver cells effectively to the pancreas do not exist. We have developed a novel catheter designed to optimize for cell delivery to the pancreas, & propose to advance this technology to the clinic.
Statement of Benefit to California: 
Bone marrow is a rich source of adult stem cells and have been utilized for over 40 years in the field of bone marrow transplantation. The use of adult stem cells, derived from the patient, or a healthy donor's bone marrow are becoming increasingly important and useful in the field of regenerative medicine. With more effective tools to enable stem cell therapy, clinicians benefit, with better, more efficient tools which make their clinical work easier and more effective . Patients benefit by having easier marrow harvests, and with better cell content, and potentially better clinical outcomes, and the Payor's benefit (i.e. California's Medi-Cal system), by providing better therapies, more efficiently at less cost with clinical outcomes that should lower overall healthcare costs. California boasts several of the world's top bone marrow stem cell transplant centers (including Stanford, UCSF, City of Hope, and others). Better bone marrow harvest technologies which ease the donation process in terms of time, inconvenience, pain and potential risks, for healthy donors (allogeneic), and for the patients themselves (autologous transplants), but should also save the hospital and insurance programs money, by taking harvests out of the operating room, and into a rapid , minimally invasive outpatient procedure. In terms of the growing field of regenerative medicine, many new approaches to treating disease utilizing marrow derived cells are showing promise, including for the treatment of heart attacks, congestive heart failure, peripheral vascular disease, and more recently for neurologic disease and injury (ie Parkinson's) and spinal cord injury. In order to enable bone marrow derived stem cell therapies, tools for the clinician (such as proposed in this CIRM application) are critical to make the process of obtaining the marrow cells (harvest), and subsequent cell processing (to isolate stem cell component) and organ specific delivery.
Review Summary: 
This proposal focuses on the development of technologies to improve the harvesting, processing and delivery of bone marrow stem cells. The Principal Investigator (PI) has recently developed a device for harvesting bone marrow that is minimally invasive compared to current techniques and yields ten times more stem cells when tested in a preclinical model. The first aim of the proposal is to develop a second-generation device for manufacture and preclinical testing. The second aim is to develop a novel device to isolate bone marrow mononuclear cells. The last aim is to optimize a novel catheter developed by the PI for direct delivery of stem cells to the pancreas. The reviewers felt that this proposal could have a broad impact on the clinical use of adult stem cells. However, they raised questions about its feasibility and lack of preliminary data. The reviewers found the research team well qualified to carry out the proposed research. The reviewers agreed that, if successful, this proposal would have significant impact on the clinical use of bone marrow derived stem cells. Stem cell therapies using adult sources are critically dependent on efficient harvesting, processing and delivery of the isolated cells. This is particularly true for bone marrow, which is a source of not only hematopoietic stem cells but also mesenchymal stem cells and endothelial progenitors. Current methods for bone marrow stem cell harvesting are painful and inefficient. The work outlined in the first aim of the proposal would significantly enhance the yield of stem cells from bone marrow aspirates while allowing the procedure to take place under local anesthesia rather than general. Reviewers were not as confident in the potential impact of the second and third aims. They were not convinced of the promise of the cell separation technology or of the compelling need for a direct catheter to the pancreatic artery. The major concerns of the reviewers were about the feasibility of this proposal. They felt that the first aim, describing development of a second-generation bone marrow harvesting device, was well thought out, with appropriate milestones and convincing preliminary data. One reviewer was impressed that the applicants already have a FDA 510(k) regulatory approval, a significant obstacle to clinical testing. However, the reviewers were skeptical about the cell separation technology described in the second aim for the isolation of mononuclear cells from bone marrow. They felt that this aim was vague, overly ambitious, and poorly supported by preliminary data. The reviewers found the final aim, development of a pancreatic artery catheter, to be more feasible, but still commented that its experiments were not well described and no timeline was provided. One reviewer noted that from the experimental plan it is unlikely that statistically sound data would be obtained from the proposed small preclinical study. The reviewers praised the quality of the research team and its extensive experience with medical device and catheter development. The budget seems generally appropriate, although one reviewer felt that the budget should be adjusted to allow a larger preclinical study. Overall, the reviewers were enthusiastic about aspects of this proposal but raised concerns about its feasibility as a whole.
Conflicts: 

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