Funding opportunities

Genetically Engineered Mesenchymal Stem Cells for the Treatment of Vertebral Compression Fractures.

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
Funds requested: 
$19 996 735
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
Approximately 10 million people in the United States currently have osteoporosis, and an additional 34 million people are at risk for osteoporosis. Osteoporotic vertebral compression fractures (VCFs) are the most common fragility fractures in the US; there are approximately 700,000 such injuries each year, twice the rate of hip fractures. Approximately 70,000 VCFs result in hospitalization each year, consuming enormous amounts of health care resources. Currently, treatment is focused primarily on prevention. When fractures occur in patients with osteoporosis, treatment options are limited because open surgery with implants often fails. In recent years, new therapies involving injection of cement into the fractured vertebra (such as vertebroplasty) have been developed. Unfortunately, these procedures do not regenerate bone tissue and carry risks of cement leakage and emboli. Recent publications in a leading medical journal question the effectiveness of those procedures. Based on these studies the American Academy of Orthopaedic Surgeons issued a set of new guidelines and recommended against the use of vertebroplasty. We need a new biological treatment that will promote repair of such fractures in a safe and efficient manner. Our plan is to develop a therapy that uses adult mesenchymal stem cells (MSCs) that are genetically engineered to express a bone-forming gene, bone morphogenetic protein 6 (BMP6). These cells have been shown to promote bone formation and fracture repair in numerous studies. Specifically, we intend to use allogeneic ("off the shelf") human MSCs. These cells will be genetically engineered with BMP6 DNA in a virus-free method, using technology currently approved for clinical use. BMP6–engineered MSCs not only secrete BMP6 protein and promote bone formation but also differentiate into bone-forming cells themselves. This combined effect leads to fast and robust bone formation, which could be an attractive therapy for a variety of clinical conditions involving bone loss. An image-guided injection of BMP6–overexpressing MSCs into a fractured vertebra could lead to rapid fracture repair and shortened hospitalization time. We propose to use allogeneic, off-the-shelf, MSCs, which do not require the patient to undergo additional medical procedures such as bone marrow aspiration. Whereas use of autologous cells is limited by the number of cells that can be obtained from the patient, use of allogeneic cells is not limited by cell number. If successful, this therapeutic strategy could revolutionize the treatment of patients with VFCs, offering a minimally invasive biological solution. We plan to analyze aspects of efficiency and safety of use of the proposed therapy in a pre-clinical model, which will enable us to submit an approvable Investigational New Drug application (IND) to the Food and Drug Administration (FDA) by the end of the 4-year project.
Statement of Benefit to California: 
Approximately 10 million people in the United States have osteoporosis, while an additional 34 million have low bone mass. The lifetime incidence of fragility fractures secondary to osteoporosis in women older than 50 years of age is approximately 1 in 2, and that in men of the same age is 1 in 4. Osteoporosis-related vertebral compression fractures (VCFs) are the most common fragility fractures in the United States, accounting for approximately 700,000 injuries per year, twice the rate of hip fractures. Approximately 70,000 VCFs result in hospitalization each year, with an average hospital stay per patient of 8 days. Fragility fractures due to osteoporosis also place a severe financial strain on the health care industry. Estimates show there were approximately 1.5 million osteoporosis-related fractures in the United States in 2001, the care for which cost about $17 billion. Moreover, as the number of individuals over the age of 50 continues to increase, costs are predicted to rise to an estimated $60 billion per year by 2030. VCFs previously received limited attention from the spine care community. This oversight may be a result of the perception that VCFs are benign, self-limited disorders or that treatment options are limited. However, it has become clear that VCFs are associated with significant functional impairment and increased mortality, even in patients not presenting for medical evaluation at the time of fracture. Current treatment of osteoporotic patients is mostly focused on prevention of VCFs. There are few treatment options when VCFs actually occur. Since open surgery involves morbidity and implant failure in the osteoporotic patient population, nonoperative management, including medications and bracing, is usually recommended for the vast majority of patients. Unfortunately, large numbers of patients report intractable pain and an inability to return to activities. Currently there is no efficient biological solution for the treatment of VCFs. In the proposed study we will continue to develop a biological therapy to accelerate repair of VCFs. This treatment will rely on adult stem cells that have been genetically engineered to overexpress an osteogenic gene, BMP6, by using a nonviral technique that is clinically approved. It will also involve an injection of these cells into the fracture site, instead of a percutaneous injection of a polymer, which does not restore lost bone tissue. Data generated from this study could potentially revolutionize the treatment of vertebral fractures and other complex fractures in patients suffering from osteoporosis. This will benefit the citizens of California by reducing loss of workdays, duration of hospital stays, and operative costs, and by improving quality of life for Californians with osteoporosis, who are at risk for VCFs.
Review Summary: 
This proposal is focused on the preclinical development of allogeneic mesenchymal stem cells (MSCs) to treat vertebral compression fractures (VCF). VCF are deformities of the vertebral bodies of the spine, and are a common manifestation of osteoporosis. VCF may be asymptomatic, or may cause pain and other neurological symptoms. Treatment of vertebral compression fractures has evolved over the last decade. Several preventive measures and procedure-based treatments have been introduced during this period. Outcomes have varied. The candidate MSCs will be genetically modified using a non-viral technique to overexpress a bone-forming gene, bone morphogenetic protein 6 (BMP6). The concept is based on the applicant’s preclinical observations that MSCs secrete BMP protein and promote formation of new bone in several models of bone loss. The key objective of this proposal is to complete the preclinical, manufacturing, regulatory and clinical activities required to submit and Investigational New Drug (IND) application to the FDA within the four-year timeframe. Significance and Impact - One reviewer commented that the magnitude of the problem is overstated in the application. Many osteoporosis-related VCFs are asymptomatic, and often symptoms improve over time. - VCF as a first indication is too high risk; the major risk is potential for bony overgrowth, which could be catastrophic in the spinal column. -The Target Product Profile (TPP) needs to aim for a specific clinical indication within VCF (e.g. symptomatic osteoporotic or traumatic VCF; acute or chronic). - The TPP should describe a desired clinical outcome in terms of the benefit to the patient, and all benefits should be compared to a control treatment. - Several reviewers concurred that the TPP described a goal for a threshold clinical outcome that was below what would be a meaningful clinical benefit. - The TPP does not address the possibility that a patient might need multiple injections to treat multiple fractures. This has implications for the safety profile that are not addressed in the program. - It is unclear from the application how this proposed therapeutic candidate will have a better safety profile compared to other clinical interventions. Project Rationale - The data do not provide adequate evidence that injection of the therapeutic candidate into the vertebra will restore normal architecture. Several reviewers thought this was critical to achieve the desired clinical outcomes. - The rationale that MSCs modified to overexpress BMP6 will induce bone formation is valid. - Utilizing MSCs to produce BMP6 is a good approach and could overcome the manufacturing challenges of producing recombinant BMPs as a therapeutic. - The therapeutic candidate would better address bone healing in non-union fracture or other bony defects. Therapeutic Development Readiness - The program does not yet appear ready to begin preclinical development; the therapeutic candidate has not been finalized (i.e. final plasmid not chosen or produced) and the preliminary proof of concept that normal vertebral architecture can be restored has not been demonstrated. - Although MSCs may be immunomodulatory, the panel was not convinced that the gene-modified cells would be non-immunogenic. - Reviewers noted that utilizing a clinically approved source for cells and techniques/processes to produce this candidate was a good strategy to shorten the timeline to IND. - A cross-reference to the drug master file (DMF) of the original cells will not suffice for safety data in this gene-modified approach using a novel delivery mechanism. Feasibility of the Project Plan - The team needs to select and justify a preclinical model that best replicates the human condition and test the candidate in such a model. - Stabilization of the vertebral body by new bone formation and restoration of the architecture need to be assessed independently and correlated to clinical outcomes. - Preclinical models can address bone formation; but whether pain is reduced and quality of life is improved will require clinical studies. - The plan is straightforward, and in the right indication could achieve an IND within the four-year timeframe. - The plan lacked important details regarding the sensitivity of methods to detect migrating cells in biodistribution studies. - Immunogenicity was not addressed and is a concern, especially if multiple rounds of injections are given. - Preclinical toxicology studies will need to be conducted with the final therapeutic candidate and the intended delivery system for this indication. - Tumorigenicity studies seemed inadequate, given that the cells will be gene-modified and have associated risks. Principal Investigator (PI) and Development Team - PI has been working on BMP-modified MSC for bone repair since late 1990s and is a leader in the field with a strong publication record. - The Co-PI brings expertise in preclinical testing. An additional team member adds expertise with assessing bone biomechanics. - The team is supported by good product development, manufacturing, and regulatory expertise. Collaborations, Resources and Environment - Contract manufacturing for both the plasmid and the cell transduction and banking is supported by solid contractors; as well as preclinical studies. - The contract research organization that will perform the preclinical studies is qualified to perform the proposed work. Budget (Assessment of the budget was conducted separately from the overall scientific evaluation and points or concerns raised in this section did not contribute to the scientific score. This section highlights items that must be addressed should the application be approved for funding.) - CMC costs of $6.8 M were judged to be excessive given commercially available cell source. - Many consultants to the project were listed as employees.
Programmatic review: 
  • A motion was made to move the application to Tier 3, Not Recommended for Funding. Competitiveness for this complicated potential therapeutic was not judged to be strong against current simple preventive measures under development and on the market. Key preclinical data that vertebral architecture can be restored was missing, and therefore the chance for a meaningful clinical benefit is low. The panel agreed that no model or study in the plan addresses this deficiency.
  • Darin Weber
  • David Pepperl

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