Funding opportunities

Gene Targeting to Endogenous Stem Cells for Segmental Bone Fracture Healing

Funding Type: 
Early Translational IV
Grant Number: 
Principle Investigator: 
Funds requested: 
$5 185 487
Funding Recommendations: 
Grant approved: 
Public Abstract: 
Segmental bone fractures are a complex medical condition. These injuries cause great suffering to patients, long-term hospitalization, repeated surgeries, loss of working days, and considerable costs to the health system. It is well known that bone grafts taken from the patient (autografts) are considered the gold-standard therapy for these bone defects. Yet these grafts are not always available, and their harvest often leads to prolonged pain. Allografts, are "dead" bone grafts, which are readily available from tissue banks, but have very low potential to induce bone repair. We have previously shown that stem cells from human bone marrow, engineered with a bone-forming gene, can lead to complete repair of segmental fractures. However, such an approach requires several steps, which could complicate and prolong the pathway to clinical use. An alternative approach would be to gene-modify stem cells that already reside in the fracture site. We were the first to show, in a rodent model, that a segmental bone defect can be completely repaired by recruitment stem cells to the defect site followed by direct gene delivery. In the proposed project we aim to further promote this approach to clinical studies. The project will include the development of a direct gene delivery technology, based on ultrasound. We will test the efficiency of the method in repairing large bone defects and its safety. If successful, we will be able to proceed to FDA approval towards first-in-human trials.
Statement of Benefit to California: 
Segmental bone defects are a complex medical problem that often requires bone grafting. Autografts are considered the gold standard for these defects, but their usage is limited by availability and donor-site morbidity and supply. Allografts are more available but often fail to integrate with the host bone. Thus there is an unmet need in the field of orthopedic medicine for novel therapies for segmental bone fractures. We propose to develop a novel approach for the treatment of such fractures without the need for a bone graft. Specifically, we will utilize ultrasound to deliver a bone-forming gene to stem cells that will be recruited to the defect site. As we have already shown, the gene would trigger the cells to regenerate the bone that had been lost due to trauma or cancer. If successful, this project could lead to the development of a simple treatment for massive bone loss. Such a treatment 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 complex segmental bone fractures.
Review Summary: 
This application for a Development Candidate (DC) award is focused on a combination product for the treatment of segmental bone defects. The combination product is comprised of a biodegradable collagen scaffold, a plasmid encoding a bone forming growth factor, a contrast agent for ultrasound imaging, and an ultrasound system to deliver the plasmid into endogenous progenitor cells. Autologous bone grafts are the gold standard for the treatment of segmental bone defects but may not always be available and are associated with comorbidity at the bone harvest site. The applicant proposes to develop the direct gene delivery technology and demonstrate proof of concept for gene delivery to progenitor cells in a laboratory model. In addition, the applicant proposes to test the safety and efficacy of the combination therapy in a clinically relevant model of bone loss, to develop a preliminary clinical plan, and to discuss the data package in a pre-pre Investigational New Drug (pre-pre IND) meeting with the Food and Drug Administration (FDA). Objective and Milestones - The Target Product Profile (TPP) is well thought out and reasonable. - The proposed risk benefit proposition is to be as efficacious with potentially less risk that the “gold standard” of care, autologous bone grafting. - The milestones are achievable within the 3-year project timeframe and address technical hurdles. Rationale and Significance - The preliminary data as well as the supporting data with bone forming growth factor variants provide sufficient rationale for the proposed approach and indication. - The evaluation data for the choice of the scaffold is not presented in the application. - This approach has the potential to minimize some known risks with conventional therapy and other cell and gene therapy approaches under investigation. - The overall approach is not novel, but targeting endogenous progenitor cells may obviate the need to manufacture cells in addition to the recombinant protein. - The approach carries a risk that relying on the recruitment of endogenous cells to the bony defect will be variable from patient to patient. Feasibility and Design - The application contains preliminary data supporting many aspects of the approach. However, in some cases adequate control data were not provided. - The plan, if executed, would lead to a data package that could be submitted and reviewed in a pre-pre IND meeting with the FDA. - Non-invasive methods are available and incorporated into assessments. - The clinically relevant, weight-bearing model is viewed as a strength of the plan. - Reviewers did not reach consensus as to whether the study in the weight-bearing model should be increased to reach statistical power or whether a small study as written should be conducted first to determine if a desired biologic outcome is achieved. - Multiple doses of the gene and off-target effects will have to be monitored carefully. - Details of specimen collection and histologic readouts were not detailed in the application. - It will be important to use the same materials and devices in the clinically relevant model study as will be proposed for the initial clinical trial. Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - The applicant has the appropriate expertise and is clearly committed to this area of research. - The team has the necessary expertise to execute the proposed plan. Additional expertise in biostatistics may add strength to the preclinical study design. - The budget is appropriate. Collaborations, Assets, Resources and Environment - The investigator has a pending patent for the approach to bone regeneration. The applicant states that the patents for the bone forming growth factors have expired. - The resources at the applicant institution are sufficient to conduct the proposed research. - The applicant has initiated negotiations for use of the scaffold and delivery method components in clinical studies. Licensing agreements will be important to secure for use in clinical studies. Responsiveness to the RFA - Reviewers judged the application to be responsive to the RFA. A target for intervention is identified.
  • David Pepperl
  • Mark Noble

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