Funding opportunities

A Wnt-based therapy targeting endogenous stem cells to enhance skeletal healing in the elderly

Funding Type: 
Disease Team Therapy Development III
Grant Number: 
Funds requested: 
$15 405 226
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
WNTs rank among the most powerful and ubiquitous stem cell factors, and their use for bone regeneration provides unprecedented opportunities. The strength of our proposal rests in the central role that WNTs play in tissue development, repair, and regeneration. WNT signaling is required for the healing of almost every tissue in the human body, and a critical insight into the mechanism of WNT action came with the discovery that in an injury site, WNTs activate adult, tissue-resident stem cells. These stem cells self-renew and divide, and in doing so give rise to progeny cells that mature into bone-forming osteoblasts. If WNT signaling is temporarily increased then the adult stem cells generate more progeny, and the progeny mature faster into osteoblasts. The end result is faster bone healing. Collectively, these studies provide compelling scientific validation for a WNT protein-based approach to enhance bone healing. There are obstacles, however, to using WNTs as therapeutic proteins. WNTs have been problematic to produce, and difficult to deliver in a controlled manner. Both issues have hindered their development as a stem cell-based regenerative medicine therapy. We have overcome these barriers: we can now generate a stable form of WNT3A protein that has demonstrated ability to activate stem cells in a patient’s own bone marrow. When these activated cells are re-introduced into a patient’s bony defect, the time to bony union is accelerated. This strategy represents a novel approach to bone regeneration. Rather than relying on metal hardware, artificial scaffolds, or cultured cells from other sources, our approach takes advantage of the solution that Nature itself developed for repairing damaged bones. Faster bone healing means a quicker return to activities of daily living but there are advantages far greater than this: Medicare data clearly show that when an older person sustains a bone injury it becomes increasingly difficult to live independently. Even if elderly patients are otherwise healthy, the risk of dying is nearly tripled by simply having a broken bone. Thus, our proposal addresses a present and ongoing challenge to healthcare for the majority of Californians, with a novel therapeutic strategy that mimics the body’s inherent repair mechanisms. If successful, this WNT based strategy will represent the first protein therapeutic that targets the activation of adult stem cells for the purpose of tissue regeneration.
Statement of Benefit to California: 
We are an aging Nation. In California alone, one out of every 3 people will be above the age of 50 by 2032. Growing old has advantages but the bad part is that our bodies- and in particular our skeletons- begin to wear out. When an older person sustains a bone injury it becomes increasingly difficult to live independently. Even if elderly patients are otherwise healthy, the risk of dying is nearly tripled by simply sustaining a broken bone. Traditional treatments for bone injuries such as casting and internal fixation (plates, rods, screws) often fail in older patients because of an unavoidable decline in bone-forming (osteogenic) capacity that naturally happens as we age. Surgeons must then turn to alternative strategies; chief among these are bone grafts from our own cells, but even this “gold standard” is unpredictable in older patients. Clearly, there is a need for safe, bone-promoting factors that can effectively enhance skeletal tissue formation and restore older patients back to health. Our WNT-based approach represents a significant and novel improvement over existing technologies and is predicated on the ability to activate a patient’s own stem cells for the purpose of bone healing. All adult tissues contain stem cells. Some tissues, like bone marrow, harbor more adult stem cells; other tissues have fewer. When a tissue or organ is injured, these tissue-resident stem cells are activated and contribute to the healing process. In the end, the ability of a tissue to repair itself after injury seems to depend on how many stem cells reside within a tissue, and the state of those stem cells. Stress, disease, and most importantly aging all diminish the capacity of adult stem cells to self-renew and proliferate, which in turn hinders tissue repair. We have developed a WNT-based approach to accelerate bone healing. WNT proteins are critical regulators of bone turnover, and abundant scientific data supports a role for these proteins in promoting bone regeneration. WNT3A is a powerful stem cell factor, and when a patient’s bone marrow is exposed to a liposomal formulation of this WNT3A protein, stem cells within that marrow become activated. If this marrow is then used in a bone grafting procedure the activated cells survive better, which translates into an improvement in engraftment efficiency. Cells in the activated bone graft also express significantly higher levels of anabolic osteogenic markers and they mature faster into bone-forming osteoblasts. As a consequence, bone defects treated with WNT-activated cells heal faster. This WNT-based strategy represents the first time a protein therapeutic has been designed to activate adult stem cells for the purposes of tissue regeneration. Its impact on human health will be staggering if this straightforward WNT formulation proves effective.
Review Summary: 
EXECUTIVE SUMMARY The goal of this Early Translational Allowance Pathway application is to complete the preclinical work necessary to develop a therapeutic candidate to enhance skeletal healing in the elderly. The therapeutic candidate consists of a combination product of autologous bone marrow aspirate that is treated ex vivo with recombinant WNT3A protein packaged in stable formulation, and is then surgically applied at the site of a bone defect to stimulate healing. The preclinical work proposed will include process development to determine Good Manufacturing Practices (GMP)-compatible conditions for scale-up manufacture and formulation of recombinant WNT3A protein, and assay development to assess purity, potency and stability of the protein. Following proof of concept efficacy and pilot safety studies and a successful preIND (Investigational New Drug) meeting with the Food and Drug Administration (FDA), GMP manufacture of the formulated WNT3A will be completed and will be tested in Good Laboratory Practices (GLP) toxicity and tumorigenicity studies. Upon successful completion of this work, an IND application will be filed with the FDA to get approval to initiate clinical studies in humans. Significance and Impact - Since there are already methods for Spinal Fusion (SF), and most grafts work, reviewers felt that it is not a major unmet need and that it would be difficult to show improved efficacy compared to a regular bone graft, the current standard of care. - Osteonecrosis of the Hip (ONH) represents more of an unmet need, as the only current therapeutic option is hip replacement surgery. - The optimal and minimal efficacy described in the Target Product Profile (TPP) was very modest, not much better than standard of care (SOC). The targeted efficacy needs to be much better than SOC due to the likely higher cost of the proposed therapeutic. Scientific Rationale and Risk/Benefit - The use of recombinant WNT3A to stimulate bone growth is a scientifically valid approach, based on published work from this group as well as on strong pre-clinical data presented in the application. These data suggest that WNT3A treatment of bone marrow aspirate improves the bone formation ability of the aspirate. - Preclinical safety studies to date suggest that potential risk to subjects is manageable. Therapeutic Development Readiness - The preclinical efficacy data provided in multiple different models of bone formation are very good, but did not include models of the proposed indications, SF and ONH. - The process for manufacturing the stable formulation of WNT3A and associated safety studies should be discussed with the FDA to be sure that the process is in line with FDA expectations. It is critical to demonstrate the feasibility to manufacture sufficient quantities of the desired purity and activity. - Reviewers questioned the specificity and sensitivity of the cellular reporter assay proposed to measure activity of the WNT3A and they felt that further characterization and validation of the assay using a preclinical efficacy model is needed. Design and Feasibility - Reviewers were very concerned about the feasibility of the proposed manufacturing process, specifically the complexity of GMP manufacture of and associated release assays for the proposed stabilized formulation of WNT3A, saying that other similar efforts have frequently proved very challenging, that a high level of expertise is required and that therefore the manufacturing budget was likely to be insufficient. - Some reviewers felt the IND-enabling plan is too lengthy and that it could be accelerated. - Reviewers were favorable of the plan to use the WNT3A protein ex vivo only. Principal Investigator (PI), Development Team and Leadership Plan - The team is strong for preclinical efficacy work and has good consultants for the biologics manufacturing. However, they lack expertise in process development/manufacture of the proposed stabilized formulation for WNT3A protein and have not selected a CRO that would manufacture the protein. - The quality of the regulatory support provided by their consultant was questioned. For example, reviewers felt a pre-pre IND meeting should be held much earlier than waiting until Year 3 as is proposed. Budget - The budget seems low for manufacturing this stabilized formulation of WNT3A, and for the costs of release assay development and validation. Collaborations, Assets, Resources and Environment - The CROs and CMOs being considered for this project generally have the required expertise. - The home institution of the PI and Co-PI is an outstanding environment.

© 2013 California Institute for Regenerative Medicine