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

Funding Type: 
Disease Team Therapy Development III
Grant Number: 
DR3-07123
Investigator: 
ICOC Funds Committed: 
$0
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.

© 2013 California Institute for Regenerative Medicine