Funding opportunities

Harnessing Native Fat-Residing Stem Cells For Spine Fusion: From Early Translation To Disease Team

Funding Type: 
Disease Team Therapy Development III
Grant Number: 
DR3-07000
Funds requested: 
$18 861 314
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
Traumatic injuries often result in permanent disability and exact a large toll on the global health burden. In many cases, skeletal injury can be so severe that it overwhelms the natural healing capacity. Especially at risk are the elderly who are prone to a higher incidence of osteoporosis, the bone weakening disease associated with an increased risk of fractures. Changing demographics and longer life expectancies are expected to increase the annual osteoporotic fracture costs to $240 billion worldwide by 2040. We are addressing this urgent need to replenish healing capacity by combining a natural cell source and bone forming stimulus to optimize safe bone regeneration. Current stem cells on the market, such as mesenchymal stem cells (MSC), require 3-4 weeks of culturing and manipulation in a lab before they can be used. Such a lengthy exposure to animal products within the culture bath risks the introduction of infectious agents and the transformation into pre-cancerous cells. Worse, the actual composition of MSC is usually unknown and partially undetermined. In contrast, perivascular stem cells (PSC) that naturally surround arteries and veins can be easily purified within a day, without need for cell culture. With the support of a CIRM Early Translational Grant (2011-2014), PSC obtained from 145 fat tissue harvests were fully validated in terms of markers for safety and bone-forming efficacy. In sum, PSC efficiently form new bone, demonstrating the capacity to repair severe bone lesions or fuse vertebrae in animals. To amplify the ability of PSC to form bone, we are delivering a natural bone stimulant called NELL-1, which has been shown to be safe and effective in large animal models, including sheep. The combination PSC+NELL-1 product allows for safer and more targeted bone formation than current standards of care. The goal of the present project is to file an Investigational New Drug (IND) application with the Food and Drug Administration (FDA) to use the PSC+NELL-1 product for spine fusion. The development of PSC has broad implications for human disease beyond bone regeneration. PSC are easily isolated and stored: in theory, an individual supply for each patient can be saved for later use. Moreover, as a ‘platform technology,’ PSC, when given the proper stimulant, can regenerate multiple different mesenchymal tissues, including bone, fat, cartilage, muscle, and even nerve. Studies are on-going for their use in cartilage and heart muscle repair / regeneration. NELL-1 protein also has significant use beyond bone repair. It has been proven effective in the regeneration of cartilage, and as a non-toxic anti-inflammatory molecule, it may be tremendously useful in treating osteoporosis without any of the harmful effects of current osteoporosis drugs. In sum, we expect the development of the PSC+NELL-1 product to have far reaching medical benefits beyond the simple regeneration of bone.
Statement of Benefit to California: 
This proposal describes IND-enabling preclinical studies for a combination product with proven superiority to current bone graft substitutes. Twenty-seven months after initial funding by CIRM Early Translational Grant, we have successfully attained all milestones, and our Developmental Candidate now provides a full package of progenitor cells, bone growth factors, and a scaffold to “jump start” bone formation. In addition to its scientific and clinical impact, this project has many near- and long-term benefits to the State of California: 1. Musculoskeletal injuries and diseases are the leading cause of work-related and physical disability in the United States. California generates an annual GPD of $1.8 trillion, making it the eighth largest economy in the world. By promoting bone repair, our mature technology will reduce: the loss of work productivity; work disability costs; and the loss of state income tax. 2. The natural decline in the number of osteogenic stem cells (from 1/10,000 in new born bone marrow to 1/2,000,000 by age 80) is associated with osteoporosis and fragility fractures in the aging population. In 2005, the health care burden for osteoporosis exceeded $1.4 billion in California alone,. By treating existing fractures and preventing new ones, this platform technology can significantly reduce the long-term health care burden for California’s public health insurance program. 3. This project directly adds jobs in the California-based companies involved. Of note, an estimated $18 million dollars of out-of-state funding has been generated over the last three years for research on PSC+NELL-1. This extra funding represents an External:CIRM funding ratio of 3.8:1. 4. This project has produced – and will produce more – intellectual property. Our team has a track record of attracting private investment and procuring supplies and equipment from strategic California-based companies. 5. This project is precisely the type of cutting-edge, multi-disciplinary stem cell therapy that Californians imagined when they approved proposition 71 in 2004. CIRM has transformed the research infrastructure, increased our ability to recruit world-class stem cell scientists, and attracted the attention of superb scientists from other disciplines to this new field. Our team has compiled an impressive list of accomplishments and we are confident in our ability to file an IND submission in a timely fashion. Funding of this project will fulfil the promise of proposition 71. 6. PSC is a ‘platform technology’ that can be optimized for the regeneration of other mesenchymal tissue, including adipose, muscle, cartilage and even nerve. Current development of PSC-based applications includes both heart and cartilage regeneration, representing an additional and outstanding potential benefit to the State.
Review Summary: 
EXECUTIVE SUMMARY This proposal will develop a combination product to facilitate spine fusion, which is a surgical procedure used to stabilize movement of two adjacent vertebrae in the spine. The proposed product is comprised of perivascular stem cells (PSCs) isolated from fat tissue combined with a bone-stimulating protein, named NELL-1, and a matrix material to improve bone formation and better stabilize the spine. The investigators propose to complete all preclinical and product manufacturing and characterization activities to enable advancing to a clinical trial with this development candidate. This application was submitted through the Early Translational Allowance Pathway, with an objective of developing and implementing GMP production and associated analytics, completing preclinical studies and filing an Investigational New Drug (IND) application with the Food and Drug Administration within the award period. Significance and Impact - Spine fusion is a common procedure in which the approved protein BMP-2 is often used, despite some safety concerns that BMP-2 can be associated with ectopic bone formation. Since currently available therapies are effective, any new therapy would need to show a substantial benefit over already approved options. - In order to have an impact relative to existing therapeutic options, an approach such as the combination of PSCs and NELL-1 with the matrix material will have to show both cost effectiveness and enhanced risk/benefit for such a complex and likely expensive approach to have a meaningful impact. - The proposal argues that the therapeutic approach will be highly cost-competitive with commercially available bone forming protein based on a misleading estimate of the cost of goods that excludes facilities, equipment, and personnel, which are typically the majority of the cost for a cell-based therapy manufactured in compliance to FDA requirements. - The Target Product Profile is well developed. Scientific Rationale and Risk/Benefit - The rationale for development of the complex combination product was not strong. There was not sufficient evidence to show that the PSCs/NELL-1 on the matrix yields a sufficiently greater response than NELL-1 on the matrix to justify the added complexity and cost of the PSC/NELL-1 combination. Since all of the components of the system appear to be targeting the same biologic response, it must be convincingly shown that all of the components of the combination product are required and superior to each one of them alone to achieve the desired effect. - It is not clear why the PSC cells are required when the NELL-1 protein alone appears to be a good development candidate, with demonstrated bone forming activity and specificity which may improve patient outcomes over the currently used bone forming protein. -There was not good rationale for the cell purification method included within the manufacturing process. Therapeutic Development Readiness -The PSCs isolated from fat are purified as two separate populations both of which contribute to the final product. There was no information provided on the proportion of the two populations in the final product, which will affect the therapeutic dose and must be tested. Moreover, it was not shown that the PSC purification process, which is a significant and costly aspect of the manufacturing, is necessary. - The proposed approach requires an experimental delivery device, but it was not clear when it would be available relative to the proposed preclinical studies and the IND filing. Design and Feasibility - The proposed model of cell purification on a patient-specific basis at the point of care in a manner that will meet regulatory requirements and within the targeted processing time will be extremely challenging. Furthermore, the estimated time required to complete the process is not realistic. - Timeline of the proposed activities was viewed as overly aggressive, especially with respect to the activities related to development of the manufacturing process and assays. -Milestones are reasonable and well written. Principal Investigator (PI), Development Team and Leadership Plan - The PI and team have the appropriate expertise to carry out the proposed activities. Budget - The budget was viewed as somewhat high for the proposed activities. Collaborations, Assets, Resources and Environment - Collaborations and resources are appropriate to complete the proposed studies. - A collaboration with an industry partner that will be important for development of the cell isolation and purification process is not yet finalized.
Conflicts: 

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