Funding opportunities

Targeting bone homing of osteoprogenitors by high-affinity ligands to enhance bone regeneration

Funding Type: 
New Faculty II
Grant Number: 
RN2-00949
Funds requested: 
$2 114 450
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
Osteoporosis is disease characterized by progressive bone loss that predisposes bone to fracture. Bone loss, a sequelae of aging or with menopausal, results from both altered bone balance with increased bone break downs and with inadequate compensatory bone formation. Mesenchymal stem cells (MSCs) in bone marrow are groups of cells that can differentiate into bone forming cells. Bone regeneration by induction of bone formation from MSCs offers a rational therapeutic strategy for preventing osteoporosis. However, direct infusions of MSCs failed to yield bone forming response due to the inability of MSCs migrate to the bone surface. There are committed bone forming cells within MSCs that can be potentially stimulated to differentiate into functional osteoblasts, the cells that make bone, if they were homed to the bone surface. Therefore, we hypothesize that bone marrow progenitor cell (MSC) attachment and osteogenic differentiation would be achieved when they are “guided” to bone surface that is rich in bone growth factors that are stored in bone matrix. To do this, we will apply the one-bead-one-compound (OBOC) combinatorial library method to identify small molecule ligands that specifically target the osteoblastic progenitors within the MSCs. Millions of peptide and peptidomimetic coated beads will be screened with enriched population of osteoblastic progenitor cells. Beads that bind strongly to these cells will be isolated for structure determination. After optimization, these ligand(s) will be conjugated to a bisphosphonate, which have high affinity to bone, will act as a "vehicle" to bring the compound together with the bone forming cells to bone. “Homing” of bone forming cells to bone surface is crucial, as this optimized ligand will be “bone forming” specific. We will determine the efficacy of the ligand in bone regeneration using various animal models of osteoporosis. We believe the ligands that are developed can be used to greatly promote bone regeneration and provide novel treatment options for bone diseases such as osteoporosis and bone trauma repair.
Statement of Benefit to California: 
Osteoporosis is considered a degenerating disease of bone. Fifty percent of women over 50, and 25% of elderly men in the USA are at risk of having an osteoporosis related fracture during their lifetime. Low bone mass (osteopenia) is the most significant predictor of future fractures, with over 1,250,000 fractures annually at a cost of $47,000 per day. In California, the aging population is rapidly expanding such that there are estimated to be more than 55,000 osteoporosis-related fractures, costing more than $2.4 billion annually (California Department of Health Service). Apart from the primary osteoporosis that result from aging or with menopausal, secondary metabolic disorders derived from chronic conditions, such as malnutrition, endocrine disturbances and chronic inflammation also impair bone metabolism and decrease bone mass. Medications, such as glucocorticoids that are widely used for the treatments in numerous pediatric and rheumatoid illnesses, generally impair bone cells activities, bone quality and increase fracture risk in children and in adults. Other therapies, like anticonvulsants , immunosuppressive agents , chemotherapies and radiation , all have adverse effect on bone. These advances in medicines have created a new population with secondary osteoporosis and osteoporotic fractures /disabilities who would otherwise wouldn't survive from their original illness. The costs for treating these groups of "secondary" osteoporosis are rasing rapidly. Therapeutic agents that are approved by FDA for osteoporosis are limited to a class of drug call "anti-resorptive agents". This class of drugs, while reducing further breakdown of bone tissues, do not restore the lost bone structure and do not increase the bone mass or strength. Only one bone active drug, human parathyroid hormone (1-34) (hPTH(1-34)), is approved FDA for osteoporosis treatment. However, PTH is not bone specific and has many side effects including its well-know effects on systemic calcium metabolisms. Therapeutic modalities that target bone formation by either increasing the number and or the activity of bone forming cells may be a more attractive approach for treatment of osteoporosis. Therefore, we propose a highly feasible method to screen the specific ligand for osteoblastic progenitors in bone marrow. This ligand (or ligands) will guide the osteoblastic progenitors to bone surface when it is conjugated to a bisphosphonate, which have high affinity to bone, will then bring the osteoblastic progenitors to bone. “Homing” of osteoblastic progenitors to bone surface is crucial, as this optimized ligand will not only be “bone” and “osteogenic” specific, but also spare the other cell types. If our proposed study is successful, the ligands that are developed can be used to greatly promote bone regeneration and provide novel treatment options for bone diseases such as osteoporosis and fracture repair.
Review Summary: 
The focus of this application is the significant medical problem of osteoporosis, a common denominator of aging, due to increased active resorption of bone and reduced regenerative repair of bone. The applicant notes that mesenchymal stem cells (MSC) have potential to regenerate bone, but that clinical application of MSC has been limited by failure of injected MSC to home to the bone surfaces where they are needed. For this reason, the applicant proposes to use a combinatorial library of compounds that bind to important surface receptors on bone surface, to identify chemicals that bind these receptors. Then armed with this information, the applicant proposes to attach the candidate binding proteins to another chemical with known high affinity for bone. These protein combinations will be tested for their ability to direct bone progenitor cells to the surfaces of bone where they can then initiate regenerative processes. The choice of the target disease was considered a strength of the application, since current therapies for osteoporosis are not really regenerative, and the proposal was also deemed innovative. The applicant’s grounding in the basic science of osteoporosis and bone biology was also a strong feature of the proposal, and for this reason, a broader discussion of how the applicant envisioned translation of the results to humans would have been welcomed. The serious weakness of the planned research was that it relied on a series of assumptions which were not supported by either a description of the literature or by preliminary data; these assumptions included, for example, the choice of particular receptors, no acknowledgement of potential toxicity of the methods to the cells, lack of calculations of the kinds of cell numbers necessary to effect a change in diseased bone, and inadequate studies on binding characteristics of the major candidates to be examined. Thus the plan overall was considered risky and of questionable feasibility. Reviewers were concerned that the applicant’s track record as an independent investigator was not strong, and that this inexperience was reflected in the lack of detail offered in the application. The insufficient detail limited reviewers’ ability to judge the quality of the research plan. The applicant has worked well as a collaborator, and has been quite productive in terms of publications. The applicant received an MD in China and did residency training there, coming to the US for basic science training in a top lab in 1997. The applicant worked as a research associate at a prestigious medical center, and has been an assistant professor (non-tenure track) since 2005 at another strong center. Reviewers were somewhat concerned about the true independent status of the applicant, and local principal mentors did not supply support letters. The institution states that requisite protected research time will be provided but does not state an actual percentage. The institution did make a clear commitment of research space and mentoring. The environment for studying stem cells in the context of bone biology is excellent. In summary, the reviewers agreed that the potential of MSC for repair of bone in the context of osteoporosis was a worthy area of study for an applicant with a strong foundation in this area, but thought that the research plan was flawed, limiting enthusiasm for the proposal.
Conflicts: 

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