Disease Team Therapy Planning I
The availability of materials to treat slow or nonhealing bone defects is a significant clinical challenge for the more than 600,000 bone graft procedures performed annually. As an alternative to the gold standard of grafting bone from the patient themselves, which is limited by extensive tissue loss and limited availability, we propose to produce functional bone tissue from unrelated donor bone marrow-derived mesenchymal stem cells (MSCs). MSCs will be seeded on biodegradable implants fabricated from FDA-approved polymers and synthetic minerals and maintained in a bioreactor that applies force to the cells for promoting bone formation on the implant. The bioreactor will be developed, housed, and maintained under Good Manufacturing Practice (GMP) standards, thereby allowing the production of a construct for implantation in human patients. We will determine the importance of these forces on the secretion of bone-like mineral by human MSCs when seeded on our engineered implants, as well as other parameters including the volume of implantable bone that can be created and degradation of the underlying polymer. The resulting cellularized implant will then be infused with cells isolated from adipose tissue (stromal vascular fraction), recently shown in two clinical trials to promote vascularization, cell survival, and improve tissue function. The capacity of the engineered construct to promote bone healing will be validated in rodent and sheep models of bone repair widely used by our group. Together with input from the FDA, successful results from small and large animal models will provide the blueprint for the appropriate development candidate to test in a Phase I/II clinical trial. The properties of our single development candidate, primarily derived from human cells, will be similar to that of native bone with regard to stiffness and mineral content. We anticipate this implant will integrate with surrounding bone much better than other currently available materials while eliminating tissue morbidity. Unlike other implants such as metals and pure bioceramics, this implant will resorb over time while functioning as native bone. The infusion of the mineralized tissue with cells from the patient’s own fat tissue before implantation will offer a patient-specific component to accelerate vascularization and enhance graft survival. We anticipate initiating the clinical trial within the period of this award due to the FDA’s familiarity with the individual components of the development candidate and our team’s broad experience with MSCs and engineered biomaterials for bone repair in a number of small and large animal models.
Statement of Benefit to California:
Congenital bone abnormalities, bone loss, and defects resulting from trauma pose a significant health problem that impacts individuals across their lifespan. Many of the most severe fractures have significant bone loss and require surgical treatment to restore function. Conventional therapies for bone-related abnormalities commonly require the grafting of bone segments into the defect (more than 600,000 procedures annually at a cost of more than $5 billion), yet a lack of sufficient material often precludes such therapies. Moreover, at least 10% of all bone defects are nonhealing, with an even higher prevalence of nonunions in the elderly. Given that at least 20% of California’s population will be over the age of 65 by 2025, it is imperative that new approaches to bone repair are developed. This proposal has two primary goals. First, we seek to develop a novel approach for generating functional pieces of implantable bone using mesenchymal stem cells (MSCs) from unrelated donors by combining MSCs with an engineered resorbable implant stimulated by a bioreactor to promote bone formation. Second, we propose to complete IND-enabling studies and carry out a Phase I/II clinical trial to treat traumatic, critical size bone defects or as an alternative to autogenous grafting for fractures than have failed to heal. Successfully achieving these primary goals will benefit the State of California and its citizens in several ways. Our findings will likely provide a novel means to treat nonhealing and traumatic bone defects by developing a novel bone graft. Clinical utilization of this system could markedly accelerate limb salvage, reduce the need for repeated surgical procedures, and conceivably improve the quality of life for these patients. These approaches could also have value in other health conditions where accelerated bone formation is warranted including osteogenesis imperfecta and osteoporosis. Also, the versatile technology developed here will have applications to other tissue engineering approaches that could benefit the biotechnology companies of California investing in regenerative medicine. Finally, we anticipate that the proposed studies will also directly benefit young scientists and researchers in training among the respective collaborating laboratories. Exposure of students to novel stem cell-related research may provide the greatest benefit to California by inspiring future leaders in science to pursue their research efforts within the state or develop products and therapies at California-based biotechnology companies.
EXECUTIVE SUMMARY Project Synopsis The goal of this effort is to develop a new therapeutic option for the treatment of non-union bone fractures or other orthopedic injuries resulting in significant bone loss. The proposed therapeutic is a tissue engineered bone product consisting of allogeneic bone marrow-derived mesenchymal stem cells (MSCs) seeded onto a scaffold and cultured in a perfusion bioreactor under osteogenic (bone-forming) conditions, leading to bone formation in vitro. The engineered bone will then be infused with autologous stromal vascular fraction (SVF) adipose cells to promote vascularization, followed by implantation into the bone defect. The applicant intends to complete investigational new drug (IND)-enabling studies, file an IND with the Food and Drug Administration (FDA), and perform a Phase I and a Phase II clinical trial during the research award period. Significance and Impact - Since non-union fractures are a significant problem, especially for the elderly, the proposed product would address an unmet medical need. - A good tissue engineering solution to the treatment of bone defects would be valuable, as a significant number of patients either cannot be treated by standard bone grafting methods or fail to respond to therapy, leading to severe outcomes, including amputation. - It is reasonable to assume that the proposed product would be used for difficult to treat or salvage cases. Given its complexity, it is hard to imagine significant first line usage. - The scope of this RFA includes engineered tissues but excludes the use of unmodified MSCs and adipose stem cells. While the tissue engineering component renders the proposed product in scope with this RFA, the applicant did not provide sufficient evidence to convince reviewers that this aspect of the product is necessary to create an efficacious therapy. Project Rationale and Feasibility - The therapeutic candidate, as described, represents a reasonable approach for the proposed indications. At present, however, the preclinical evidence does not justify the therapeutic rationale. - The applicants have provided strong evidence that MSCs seeded onto scaffolds will differentiate to bone when implanted in vivo. However, none of their studies to date have used a bioreactor to grow tissue and it remains unknown whether such a tissue-engineered product is superior to the MSC/scaffold approach. Furthermore, no data of in vivo efficacy or safety of the proposed product, engineered bone plus SVF cells, has been provided. The proposed product is therefore not ready for preclinical development as described under this RFA. - The novelty of the proposed therapeutic lies in the inclusion of autologous SVF cells. The applicant does not, however, provide clear evidence of the SVF cells contribution to vascularization or the necessity of SVF cells to the clinical benefit of the proposed product. As their inclusion greatly raises the complexity of the proposed product, increases its development time and cost, and limits its ultimate utility in clinical practice, it is critical to understand the contribution of SVF cells to the proposed product. - It is not feasible to advance the proposed tissue engineered product from pre-clinical studies into an active IND and then complete a Phase I and a Phase II trial in 4 years. - The project does not look feasible because construction of a bioreactor for good manufacturing practice (GMP) use and definition of the tissue-engineered product have yet to start. The ratio of scaffold components and the bioreactor conditions should be defined prior to start of IND-enabling studies. - It is surprising that good laboratory practice (GLP) testing is already underway when no data seem to be available for the tissue engineering process. It does not seem possible to progress with a clinical trial of an engineered tissue when the GLP studies have investigated the cells and scaffold but not the proposed product itself. - Given the individual components of the proposed product are generally accepted to be safe, the phase I trial, as proposed, is unlikely to be informative. Anything short of a very high frequency adverse event would go unnoticed in a small study of a few patients. - Although the applicant cites evidence that allogeneic MSCs are tolerated in animal models, it is possible that allogeneic cells will ultimately be rejected, due to the fact that once they differentiate into bone, they express histocompatibility antigens. Principal Investigator (PI) and Planning Leader - The Principal Investigator (PI) is an orthopedic surgeon who has conducted or has been involved with a number of clinical trials, including ones for non-union fractures. - The PI has not been involved in the development of the candidate therapeutic; this expertise will be supplied by the Planning Leader (PL). - As a laboratory scientist, the PL has a reasonably strong academic track record. - The PL has no experience with clinical trials or filing of IND applications. The relevant expertise will be supplied by collaborators, raising the question of why this investigator was chosen for this role.
- Andrew Balber