Funding opportunities

Using Nell-1 to harness the osteogenic potential of adult stem cells

Funding Type: 
Disease Team Research I
Grant Number: 
Funds requested: 
$19 571 913
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
Traumatic injuries are responsible for over 15% of the global health burden. Many are musculoskeletal injuries that, if untreated, can cause long-term disability. Bone regeneration is a natural process that is critical for fracture repair and for the healing of bone grafts used during skeletal reconstruction. However, aging and metabolic bone diseases like osteoporosis can negatively affect the bone regeneration capacity by reducing stem cell numbers and cell activity. The failure to heal fractures in osteoporotic patients, for instance, has been reported to be as high as 50%. Osteoporosis is by far the most common systemic disease of skeletal fragility. Up to 50% women and 20% men over age 50 will suffer an osteoporosis-related fracture in their remaining lifetime. Furthermore, osteoporosis is frequently associated with other diseases like i] spinal cord injury, in which fractures are the result of limb disuse, ii] Parkinson’s disease and multiple sclerosis, in which there is an increased risk of life threatening fractures from falls, iii] malignant neoplasms invading bone that increase pathologic fracture risk and iv] organ transplant patients on chronic steroid-mediated immunosuppression. Due to changing demographics and increased life expectancy, annual osteoporotic fracture costs are projected to increase from $20 to $240 billion worldwide by 2040. Bone regeneration therapies can be cell- or non-cell based. Cell-based therapies either take the patient’s own cells (which causes significant pain and discomfort) or use cells from deceased donors. The latter requires extensive processing to remove immune components, and do not work as well as the patient’s own bone and stem cells. Non-cell based therapies are either less effective (deceased donor bone with no cells) or have undesirable effects (e.g., bone morphogenetic proteins can cause life threatening neck swelling). Current therapies also do not address the needs of osteoporotic populations where the healing environment is suboptimal and/or bone harvest from the patient’s own hip can further damage already weak bone. To address the unmet medical need, our team has developed an adult stem cell product that exceeds the efficacy and safety of current bone repair therapies. Stem cells hold great promise in their ability to regenerate damaged tissues. However, until now, stem cells have been difficult to identify and isolate in numbers sufficient for medical use without cumbersome cell culture. We have developed a highly effective and reproducible method to isolate and purify high numbers of a person’s own stem cells from fat tissues obtained through liposuction, a relatively safe and common cosmetic surgery procedure. In addition, we have developed a highly potent and bone-specific growth factor to help these stem cells form bone. Combined, the stem cell-growth factor product forms an environment that can significantly regenerate bone in normal as well as osteoporotic patients.
Statement of Benefit to California: 
This well developed proposal aims to enable IND submission for the use a novel growth factor to direct the differentiation of human perivascular stem cells within a osteogenic carrier for bone regeneration. This highly multi-disciplinary project has many near-term and long-term benefits to the State of California. 1. California’s climate is attractive to people all ages, particularly the elderly. Unfortunately, a large fraction of the aged population suffers from osteoporosis. In 1998, the health care burden for osteoporosis exceeded $2.4 billion in California alone. A whopping 64% of the $2.4 billion was caused by hip fracture. By promoting the repair of both normal and healing-impaired bone in a safe and effective manner, our mature technology will reduce the long term health care burden for California’s public health insurance program. 2. Besides direct health cost, bone injuries and diseases can result in hospitalizations and long term disabilities that can lead to sick days and lost productivity. The hard working Californians are responsible for California’s annual gross domestic product of $1.8 trillion, which rank our state among the top eight largest economies in the world. By promoting the repair of both normal and healing-impaired bone in a safe and effective manner, our mature technology will reduce the loss of work productivity at the front end, reduce work disability costs, and reduce the loss of state income tax. 3. California boasts a highly diverse population with numerous ethnic groups. While this diversity offers amazing opportunities for cross cultural discoveries, some ethnic groups (e.g. Latino and some Asian descents) may be disadvantaged in terms of donor matches for traditional stem cell sources. Our stem cell therapy can benefit these minorities and reduce the long term health care burden for California’s public health insurance program. 4. This project directly adds jobs at {REDACTED} and at the California-based companies that are involved in this project. 5. This project will procure supplies and equipment from strategic California-based companies. 6. This project will produce intellectual property that is owned by the {REDACTED}. 7. This mature project is precisely the type of cutting-edge, ethical, multi-disciplinary stem cell project that Californians imagined when they approved proposition 71 in 2004. The establishment of CIRM has transformed the research infrastructure at {REDACTED}, increased our ability to recruit world class stem cell scientists, and attracted the attention of superb scientists from other disciplines to this new field. Working together, our team has compiled an impressive list of accomplishments and we are confident in our abilities to take this project to IND submission in a timely fashion. Funding of this project will fulfill the promise of proposition 71.
Review Summary: 
This application proposes the development of a complex combination product designed to induce bone formation in either stabilized tibial shaft fracture or spinal fusion settings. The product will be composed of purified perivascular stem cells (PSCs) derived from a liposuction product from a patient combined with materials to provide an osteogenic environment. The osteogenic environment will be provided by conventional cellular or acellular allogeneic donor bone graft material that may or may not include commercially available stem cells, together with a potent bone-specific recombinant human growth factor. The product system will also include a device for cell seeding and mixing. The applicant proposes to optimize the specific cell and scaffold composition using a preclinical rodent model of impaired bone healing. Then, the applicant intends to develop cGMP-compliant processes, which would lead to pre-IND studies. If success criteria are met, the applicant will compile and submit the IND application. The reviewers noted the unmet clinical need for patients requiring repair of bone defects, such as non-union fractures and spinal fractures. The review panel noted the already established use of allogeneic cellular bone grafts and bone grafts combined with osteogenic cytokines, but they were not clear about the advantages of the proposed complex combination product over current therapies. Hence, reviewers considered the rationale for the combination product to be weak. Although reviewers expressed interest in the novel osteogenic growth factor, their enthusiasm was dampened by the applicant’s rationale for incorporating it into a combination product. They believed the application would have been strengthened by focusing on development of the growth factor alone as simplifying the proposed product would significantly reduce the complexity of proposed approach. In addition, reviewers were unconvinced by the applicant’s suggestion that use of the proposed combination product would be less costly than current treatments using BMP2. Furthermore, the review panel questioned the rationale behind choosing PSCs. Although they were intrigued by the proposal that PSCs are the original source of mature mesenchymal stem cells and acknowledged the applicant’s contribution to the literature in this area, reviewers were concerned that the concept remains a theory and is not broadly accepted by the stem cell community. Reviewers had mixed reactions about the preliminary data. They recognized the value of preliminary work with the bone-specific growth factor shown to be less adipogenic than BMP2 and to have highly specific osteogenic activity in a number of models. They noted that the applicant adequately demonstrated osteogenic and vasculogenic activity of the PSC fraction in several preclinical models. Additionally, the applicant has demonstrated that current cellular bone grafts currently in use are more osteogenic when induced by the bone specific growth factor. However, compelling evidence was not provided to indicate that bone formation with the proposed product was better than with the growth factor alone. Further data was also needed detailing the therapeutic advantages of the PSCs relative to other cell preparations that would be easier to isolate. Reviewers had concerns about the overall feasibility of the proposed preclinical research and development plan for this combination product. They thought the milestones were objective and appropriate but not necessarily achievable in the proposed timeline. The applicant has already undertaken development of the recombinant ostogenic growth factor for another application and can leverage aspects of that project. Basic formulation work on the non-cellular components of the product are already underway and can be adapted to cGMP manufacture. In contrast, reviewers considered autologous PSC dose, production and characterization to be a major unresolved issue in the proposed project. They note that the applicant did not provide sufficient details concerning the number of cells that could be derived from the patient after liposuction and presented only theoretical calculations for the yield of PSCs expected from the liposuction product, making no allowances for the known inefficiency of cell isolation by sorting or for the recovery of cells after freezing. This ambiguity regarding the dose of PSCs is not likely to be resolved until methods are established and validated. In addition, reviewers were concerned about the GMP manufacturing of sorting antibodies and questioned whether the applicant intended to develop a more robust method for PSC isolation. The manufacturing timeline did list refined PSC processing methods, but the applicant did not indicate what these refined methods would be. Reviewers considered addressing these issues as an essential component for a successful IND filing. Another troubling aspect of the proposal was the inadequate discussion of engineering activities to produce a clinically-suitable device to perform the final mixing step for the combined tissue engineered product. Reviewers conceded that two years may be sufficient time to develop such a device, but they were unable to judge the likelihood of success since necessary information was not provided in the application. Furthermore, reviewers voiced serious reservations about the use of commercial stem cells as part of the proposed product, since the impact of this component on the final product’s design, safety, and assessment of purity are unknown and would complicate the already complex regulatory issues around the combined product. In addition to the product production and characterization components of the preclinical research and development plan, reviewers also expressed concern about the proposed studies in preclinical models. They considered the number of preclinical modeling experiments for Year One daunting, and noted that the application would be strengthened if the applicant had better defined the appropriate patient population to be modeled. They highlighted the need for additional controls to confirm the value of this combination product and encouraged early discussion with the FDA to seek their input on the adequacy of the proposed models and studies. They questioned the feasibility of a successful IND filing in four years given the complexity of this combination product and the stage of development of its components. The reviewers considered the project team’s history of productive collaboration a strength of the proposal. The PI has a strong background in osteobiology and is responsible for much of the interesting preliminary work on the bone specific growth factor. However, reviewers were not confident that the assembled team could carry out a focused therapeutic development program and felt that the applicant team would benefit from individuals who could provide regular clinical advice and input related to cell therapy regulation. The budget was judged as extensive but appropriate. A reviewer noted that costs for developing GMP monoclonal antibodies to isolate PSCs in Year Two seemed excessive at this stage of development; this expense should be deferred until the applicant is certain that the combined product is more efficacious that product without PSCs. Reviewers believed the proposed collaborations would be appropriate. Although reviewers noted that the research environment is committed to translation research, there were concerns that the environment is not ideally suited for product development. In addition, the panel recommended that conversations with regulatory consultants transpire earlier than proposed and be considered a priority, and participation of contract research organizations (CROs) required more definition. The applicant proposes a combination tissue engineered product incorporating perivascular stem cells, an osteogenic growth factor, and conventional cellular or acellular allogeneic donor bone graft material together with a device for mixing the components. Strengths of the proposal included the expertise of the project team, and encouraging preliminary data. However, the review panel believed the feasibility of achieving the goal of IND filing in four years was severely compromised by the relatively early stage of product development and by the regulatory complexities this combination product would face in filing an IND application. In addition, reviewers were not convinced by the applicant’s rationale for developing a complex combination product that would be a competitive approach to the targeted indications.
  • Paul Simmons

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