Bone or Cartilage Disease

Coding Dimension ID: 
279
Coding Dimension path name: 
Bone or Cartilage Disease

Cartilage Regeneration by the Chondrogenic Small Molecule PRO1 during Osteoarthritis

Funding Type: 
Early Translational II
Grant Number: 
TR2-01829
ICOC Funds Committed: 
$6 792 660
Disease Focus: 
Arthritis
Bone or Cartilage Disease
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Other
oldStatus: 
Active
Public Abstract: 
The ability to direct the differentiation of resident mesenchymal stem cells (MSCs) towards the cartilage lineage offers considerable promise for the regeneration of articular cartilage after traumatic joint injury or age-related osteoarthritis (OA). MSCs can be stimulated in vitro to form new functional cartilage. In the OA-affected joint, the repair is insufficient, leaving a damaged matrix, suggesting that key factors are missing to properly direct the regenerative process. Molecules that activate the chondrogenic potential of cartilage stem cells may potentially prevent further cartilage destruction and stimulate repair of cartilage lesions. Currently there are no disease-modifying therapeutics available for the 40 million Americans suffering from OA. Therapeutic options are limited to oral and intra-articularly injected pain medications and joint replacement surgery. The primary objective of this project is to develop a non-invasive, therapeutic for the regeneration of cartilage in OA. This new therapy will target the resident MSCs in the joint, stimulate production of new cartilage matrix, promote repair and thus limit additional joint damage and improve joint pain and function. To provide a proof-of-concept for our strategy, a cell-based screen of a diverse small molecule library led to compounds capable of enhancing the formation of articular cartilage (chondrogenesis) from MSCs in vitro. In secondary assays, molecules were assessed for protection of the existing cartilage against induced tissue damage. Through these approaches, the lead low molecular weight small molecule PRO1 was identified which promotes cartilage differentiation and protects cartilage from damage. PRO1 reproducibly demonstrated in vivo efficacy in two animal models of OA (surgical and enzyme-induced). OA-associated pain was reduced and the architecture of the cartilage was restored. PRO1 therefore appears to activate the regenerative potential of the resident cartilage stem cells.
Statement of Benefit to California: 
Osteoarthritis (OA) is the most prevalent musculoskeletal disease and globally the 4th leading cause of Years Lost to Disease (YLD). OA affects over 40 million Americans and the magnitude of the problem is predicted to increase even further with the obesity epidemic and aging of the baby boomer generation. It is estimated that 80% of the population will have radiographic evidence of OA by age 65 years. The annual economic impact of arthritis in the U.S. is estimated at over $100 billion, representing more than 2% of the gross domestic product. OA accounts for 25% of visits to primary care physicians. In 2004 OA patients received 650,000 knee and hip replacements at a cost of $26 billion. Without change in treatment options 1.8 million joint replacements will be performed in 2015. OA is a painful, degenerative type of arthritis; physical activity can become difficult or impossible. Some patients with osteoarthritis are forced to stop working because their condition becomes so limiting. OA can interfere with a patient's ability to even perform routine daily activities, resulting in a decrease in quality of life. The goals of osteoarthritis treatment are to relieve pain and other symptoms, preserve or improve joint function, and reduce physical disability. Current therapeutic options are limited to pain medications and joint replacement for patients with advanced disease. No disease-modifying OA drugs are approved for clinical use. OA is thus a major unmet medical need with a huge clinical and socioeconomic impact and a complete absence of effective therapies. Clearly the development of a new therapeutic that is both symptom and disease modifying would have a significant impact on the well-being of Californians and reduce the negative economic impact on the state resulting from this highly prevalent disease.
Progress Report: 
  • We have carried out a structure-activity relationship study to identify highly potent analogues of kartogenin with chondrogenic and chondroprotective activities. Over 150 analogues were synthesized with structurally diverse elements and assessed for chondrogenic activity (ability to induce mesenchymal stem cells to differentiate into cartilage producing chondrocytes) on human and rodent mesenchymal stem cells. A number of highly potent lead compounds were identified which will next be assessed in chondroprotective assays, cell-based selectively and toxicity assays, pharmacokinetic assays and in vivo rodent efficacy models. At the same time a number of assays were developed and used to assess the chondrocyte protective effects, joint retention, and proliferative activity on human chondrocytes of the parent compound, kartogenin. Kartogenin was found to: (1) have long term human and rodent chondrogenic activity; (2) possess chondroprotective activity in bovine chondrocytes (i.e., protects against degradative activities in the joint); (3) minimally induce chondrocytes proliferation (an undesired activity that could lead to fibrotic and immune responses); (4) have good joint retention (compound retained in the intra-articular space at the site of action); and (5) is subject to rapid systemic clearance (a desirable property to minimize systemic adverse effects).
  • We also identified the mechanism by which the compound functions. In contrast to other drugs in development for osteoarthritis, kartogenin does not target extracellular enzymes involved in joint cartilage degradation. Rather it appears to act directly on an endogenous stem cell population and induce chondrocyte formation. The molecule binds selectively to an intracellular protein filamin A, a protein involved in regulating the cell’s cytoskeletal network (structural elements inside the cell). Rather than modulating the interaction of filamin A with other structural proteins, kartogenin blocks its interaction with the protein CBFβ (core binding factor β subunit, a subunit of a transcription complex with the runt-related transcription factor (RUNX) family). The result is an increase in CBFβ levels in the nucleus where it binds and activates transcription of RUNX dependent genes. In particular CBFβ activates RUNX1 dependent transcription of genes that play key roles in chondrogenesis. Thus this molecule acts by a novel mechanism directly and selectively on gene transcription to induce the selective differentiation of mesenchymal stem cells to chondrocytes. Importantly molecules that act by this method should complement the activity of drugs in clinical trials aimed at blocking degradative enzymes.
  • We have made excellent progress toward the identification of a preclinical candidate for the treatment of osteoarthritis. A large structure-activity relationship study was carried out with the chemical synthesis of over 250 analogues of the original lead compound. We have identified molecules with improved activity in cell culture and in relevant preclinical in vivo models. Based on these efforts we are synthesizing a final series of molecules which we will profile with respect to in vitro and in vivo chondrogenesis activity, pharmacokinetics and safety. We expect to choose the final preclinical candidate from this series in the third year of the grant.
  • Osteoarthritis (OA) is the most prevalent musculoskeletal disease affecting about 27 million people in the United States, and is the leading cause of chronic disability in the United States. Current therapeutic options are limited to pain or symptom-modifying drugs and joint replacement surgery; no disease-modifying drugs are approved for clinical use. OA is characterized by progressive degeneration of the articular cartilage, resulting from abnormal activation, differentiation and death of cartilage cells. A unique and unexplored therapeutic opportunity exists to induce somatic stem cells to regenerate the damaged tissue and reverse the chronic destructive process. Because limited joints are affected in most OA patients, intra-articular (IA) drug injection is an attractive treatment approach that allows high local drug concentration with limited systemic exposure. Targeting resident stem cells pharmacologically also avoids the risks and costs associated with cell-based approaches.
  • Cartilage contains resident mesenchymal stem cells (MSCs) that can be differentiated in vitro to form chondrocytes. This observation suggests that intra-articular injection of a small molecule that promotes chondrogenesis in vivo will preserve and regenerate cartilage in OA-affected joints. Using an image-based screen, we identified a drug-like small molecule, kartogenin (KGN), that promotes efficient and selective chondrocyte differentiation from MSCs in vitro. Intra-articular injection of KGN also shows beneficial effects in surgery-induced acute and enzyme-induced chronic cartilage injury models in rodents, as well as positive effects in incapacitance pain models. This project is aimed at the development of new lead compounds with improved biological activity, the demonstration of efficacy of the lead compounds in rodent and dog OA models and the elucidation of the cellular mechanisms underlying the cartilage regeneration activities of KGN and its analogs.
  • Through medicinal chemistry efforts, we have designed and synthesized over 400 analogs of KGN. Using cell culture based assays, we assessed the chondrocyte differentiation activity of these analogs and identified 17 compounds exhibiting improved potency compared to KGN (EC50 < 100 nM). These compounds showed no obvious cytotoxicity at high concentrations (100 μM) when incubated with a variety of cells present in the joints including MSCs, chondrocytes, osteoblasts and synoviocytes. Up to date, we have assessed the efficacy of 7 compounds using a rat OA model (medial meniscal tear). Two of the tested compounds showed significantly improved cartilage repair at the end of the study. At the same time, no adverse effects, such as body weight loss, pain or impaired motor functions, were observed in any compound treated animals. We are currently studying the effects of another 10 analogs using the same OA model, which is expected to conclude within two to three months. Next, we will assess the efficacy of active compounds in a canine OA model (partial meniscectomy using beagles). Furthermore, full rodent pharmacokinetics and non-GLP toxicology studies will be performed for the lead compounds.
  • To study the underlying mechanisms of KGN induced chondrogenesis, we designed and synthesized an affinity probe with biological activities comparable to that of KGN. Through affinity-based methods, we identified protein filamin A (FLNA) as the target of KGN. In MSCs, KGN binds to FLNA and disrupts its interaction with core binding factor β (CBFβ), which leads to the nuclear translocalization of CBFβ, subsequent activation of the RUNX1-CBFβ transcription program and, as a result, chondrocyte differentiation. This mechanism has been confirmed using cell biological methods including RNAi mediated gene silencing and cDNA overexpression of relevant genes such as FLNA, CBFβ and RUNX1. These studies have been published in the journal Science.

Harnessing native fat-residing stem cells for bone regeneration

Funding Type: 
Early Translational II
Grant Number: 
TR2-01821
ICOC Funds Committed: 
$5 391 560
Disease Focus: 
Bone or Cartilage Disease
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Other
oldStatus: 
Active
Public Abstract: 
Like most tissues of the body, bone possesses a natural regenerative system aimed at restoring cells and tissues lost to natural cell aging, disease or injury. These natural regenerative systems are complex combinations of cell growth factors and support structures that guide and control the development of specialized bone stem cells. However, the regeneration process may still fail, for multiple reasons. For instance, the degree of skeletal injury may be so great that it overwhelms the natural regenerative capacity. Alternatively, the natural regenerative capacity may be defective; this is exemplified by osteoporosis, a frequent condition affecting post-menopausal females and elderly males and females. Osteoporotic individuals have severe declines in stem cell numbers (10-fold decrease from age 30 to 80) and stem cell function (tendency of stem cells to turn into fat rather than bone cells with age), leading to bone loss and “fragility fractures” that typically would not occur in persons with normal stem cell number and function. Thus, there is a tremendous need for therapies to increase the number and function of endogenous adult stem cells with the potential to build new bone. One option is to introduce so called mesenchymal stem cells (MSC) from the patient to bone repair sites. However, significant hurdles to autologous MSC use include the need for 2-3 week culture times to isolate MSC before application. Moreover culturing introduces infectious and immunogenic risks from prolonged exposure to animal products and cancerous risks from cellular gene changes in culture. In addition, once isolated, MSC require appropriate growth factor stimulation to form bone. Finally, MSC isolated from patient tissues such as fat or bone marrow are heterogenous and of undetermined composition—making growth factor dosing and conformance with FDA regulations for defining target product identity, purity, and potency more difficult. To circumvent these problems, we have identified and purified the cells at the origin of human MSC. We have termed these perivascular stem cells (PSC) because they are natively localized around all arteries and veins, forming the key cellular component of the natural regenerative system. In a significant breakthrough, we are able to isolate these cells within hours from adipose tissues in sufficient numbers for therapy without the need for culture. This realizes the possibility of harvesting and implanting stem cells during the same operative period. In another breakthrough, we have identified a potent growth factor NELL-1 that potently amplifies the ability of PSC to form bone and vascular structures. This has led to the development of our target PSC+NELL-1 product, which effectively stimulates and augments the body’s natural bone regenerative system by providing all the components (stem cells, growth factor, and allograft bone support structure) necessary to “jump start” as well as maintain the function of bone stem cells.
Statement of Benefit to California: 
This FDA oriented proposal focuses on crucial preparatory work required before IND-enabling preclinical studies on our Developmental Candidate for bone formation and regeneration. Our Developmental Candidate provides a complete package of stem cells, bone growth factors, and scaffold to build an optimized microenvironment to “jump start” bone formation in normal and impaired bone healing conditions. We have generated very promising preclinical data on our Developmental Candidate’s superior bone formation and regeneration efficacy. In addition to its significant impact on health care, this highly multi-disciplinary project by our team has many near-term and long-term benefits to the State of California. 1. Besides direct health costs, musculoskeletal injuries and diseases are the leading cause of work-related and physical disability in the United States. 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. 2. Local osteogenic stem cells decline with age (from 1/10,000 in newborns to 1/250,000 by age 30 and 1/2,000,000 by age 80), leading to osteoporosis, poor bone quality, and fragility fractures. 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. If our Development Candidate is successful in healing existing fractures in impaired bone, it may also translate to therapies to prevent fractures in impaired bone. This will significantly reduce the long-term health care burden for California’s public health insurance program. 3. This project directly adds jobs at [REDACTED] and at the California-based companies that are involved in this project. 4. This project will produce intellectual property that is owned by t [REDACTED]. Our team has a track record of attracting out of state private investment to invest in California and of procuring supplies and equipment from strategic California-based companies. 5. This mature project is precisely the type of cutting-edge, 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.
Progress Report: 
  • Background: unsuccessful bone repair
  • Most organs can regenerate cells lost to ageing, exposure to adverse conditions, ephemeral lifespan, disease or injury. Regenerative systems are complex combinations of growth factors and anchorage molecules which support, guide and control the maturation of specialized stem cells. The regenerative process may still fail, for multiple reasons. Bone fractures will sometimes not heal spontaneously because parts of the broken bone do not join anymore, or because bone regeneration itself is impaired, like in osteoporosis, a frequent condition that affects post-menopause females and elderly people of both genders.
  • A novel class of bone-healing stem cells
  • Since specialized bone-forming cells have not been identified, which stem cells could be used for the cell therapy of bone fractures? We have identified and purified novel stem cells, localized around blood vessels and therefore named perivascular stem cells (PSCs). We have also demonstrated that Nell-1, a potent osteogenic growth factor we have developed, efficiently turns PSCs into bone cells. In 2011, we have been granted support by the California Institute for Regenerative Medicine to develop a product to heal critically fractured bones in osteoporotic – or not – patients or to perform spine fusion in order to correct skeletal defects. PSCs will be purified from the patient’s own fat tissue, a well-documented, rich source of these cells, and embedded in a biocompatible scaffold in the presence of the bone forming growth factor. The resulting compound, inserted at the site of the fracture, will provide bone-forming stem cells 1-precisely characterized in terms of origin and identity; 2- derived from the patient, hence not rejected; 3- not cultured, therefore similar to their natural counterparts.
  • Progress after one year of research supported by CIRM
  • We are now close to the end of the first year of our CIRM supported studies. In this initial period we have, first, validated the stem cells of use with regard to stringent biologic criteria: how many of these cells can be purified from fat tissue? How viable and pure are these cells after the sorting process? Do stem cell numbers and quality depend on the age, sex and corpulence of the donor? Following analysis of about 80 distinct fat harvests (lipoaspirates) we have determined that robust bone forming PSC can be reliably purified, in sufficient numbers, from male and female donors in all age and weight ranges. We have also shown that PSC are at least as good, in terms of bone forming potential, than conventional mesenchymal stem cells (the candidate stem cells, so far, to be used for cell therapies of bone defects amd injuries), while being significantly superior regarding purity and safety.
  • Transplantation experiments in mice and rats have revealed that the combination of PSC and the Nell-1 growth factor ensures the most efficient bone regeneration, but that PSC do not give rise to tumors, an important verification in any protocol involving transplantation. These experiments have also demonstrated that PSC stimulate the formation of new blood vessels, an essential requisite for efficient wound healing and tissue repair.
  • Finally, we have embarked on the development of a larger animal model of bone regeneration, that will be used in the second and third years of the projects.
  • In summary, we have reached all the milestones and met the deadlines planned in the original project. The next year will see the further validation of the protocol and the beginning of the development of a stem cell/scaffold/growth factor combination product in the perspective of trials in human patients.
  • Our research group has identified in the human body a novel class of stem cells endowed with strong osteogenic potential, which means capacity to produce bone. These stem cells are attached to the outer aspect of blood vessels, and therefore present in all organs. Our ultimate goal is to use these stem cells in human beings, to perform for instance spine fusion, a procedure used to treat spine deformities (scoliosis) or faulty vertebrae, or to heal complicated bone fractures, especially in patients suffering from osteoporosis, a condition where spontaneous bone repair is compromised. We shall harvest stem cells from the patient’s own abdominal adipose (fat) tissue, a rich source of these cells which is also easy and safe to collect. Stem cells will be purified on an automated machine, named fluorescence activated cell sorter, and immobilized on an engineered biocompatible scaffold in the presence of a novel osteogenic growth factor, that is a sort of hormone which stimulates stem cell development into bone. We have won an Early Translational grant (2011-2014) from the California Institute for Regenerative Medicine to develop this project to the stage where the first clinical trials can be engaged into. In the first year, we had fully validated the stem cell population of use on a large number of human adipose samples and clearly documented the availability, efficiency and safety of these cells independently of the age, sex and weight of the donor. We had also initiated experiments in mice and rats which have been pursued during the second year, finally demonstrating unequivocally the outstanding bone forming ability of these cells in the presence of the appropriate scaffold and osteogenic hormone. We have also, during this 2nd year, developed a large animal model of stem cell mediated bone regeneration which will be indispensable prior to the inception of human treatments. Finally, we have refined the physicochemical properties of the scaffold for optimal osteogenic factor availability and bone growth. In conclusion, all milestones and deadlines included in this grant have been met and our team is steadily progressing toward the medical “translation” of these novel stem cells.
  • Our research group has identified in the human body a novel class of stem cells endowed with strong osteogenic potential, which means capacity to produce bone. These stem cells are attached to the outer aspect of blood vessels, and therefore present in all organs. Our ultimate goal is to use these stem cells in human beings, to perform for instance spine fusion, a procedure used to treat spine deformities (scoliosis) or faulty vertebrae, or to heal complicated bone fractures, especially in patients suffering from osteoporosis, a condition where spontaneous bone repair is compromised. We shall harvest stem cells from the patient’s own abdominal adipose (fat) tissue, a rich source of these cells which is also easy and safe to collect. Stem cells will be purified on an automated machine, named fluorescence activated cell sorter, and immobilized on an engineered biocompatible scaffold in the presence of a novel osteogenic growth factor, that is a sort of hormone which stimulates stem cell development into bone. We have won an Early Translational grant (2011-2014) from the California Institute for Regenerative Medicine to develop this project to the stage where the first clinical trials can be engaged into. In the first year, we had fully validated the stem cell population of use on a large number of human adipose samples and clearly documented the availability, efficiency and safety of these cells independently of the age, sex and weight of the donor. We had also initiated experiments in mice and rats which have been pursued during the second year, finally demonstrating unequivocally the outstanding bone forming ability of these cells in the presence of the appropriate scaffold and osteogenic hormone. We have also, during this 2nd year, developed a large animal model of stem cell mediated bone regeneration which will be indispensable prior to the inception of human treatments. Finally, we have refined the physicochemical properties of the scaffold for optimal osteogenic factor availability and bone growth. In conclusion, all milestones and deadlines included in this grant have been met and our team is steadily progressing toward the medical “translation” of these novel stem cells.

Systemic Adult Stem Cell Therapy for Osteoporosis-Related Vertebral Compression Fractures

Funding Type: 
Early Translational II
Grant Number: 
TR2-01780
ICOC Funds Committed: 
$1 927 698
Disease Focus: 
Bone or Cartilage Disease
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Other
oldStatus: 
Active
Public Abstract: 
Vertebral compression fractures are the most common fractures associated with osteoporosis. Approximately 700,000 osteoporosis-related vertebral compression fractures (OVCFs) occur each year in the US. Currently, treatment is focused primarily on prevention. When fractures occur in patients with osteoporosis, treatment options are limited because open surgery with implants often fails. Recently, new therapies involving injection of cement into the vertebral body were developed. Unfortunately, these procedures do not regenerate bone tissue, but do incur risks of leakage and emboli. Hence, we need new treatments that directly address both the underlying cause of OVCFs (bone loss) and the inadequate repair mechanisms when fractures occur. We propose to develop a therapy that exploits mesenchymal stem cells (MSCs) stimulated in vivo with PTH (parathyroid hormone) to accelerate bone repair. PTH alone can accelerate fracture repair in healthy animals by activating bone marrow MSCs. However, osteoporotic patients have either decreased numbers of MSCs, dysfunctional MSCs, or both. In these patients, injection of MSCs combined with a PTH regimen could be an effective therapy for the treatment of multiple fractures. Our preliminary data in a mouse model demonstrated that this combined treatment enhances MSC homing to long-bone fracture sites and leads to increased repair. Here, we will build upon this foundation and ask whether a similar strategy is also effective in OVCFs. We hypothesize that PTH administration will lead to increased homing of MSCs to sites of bone fracture. We further hypothesize that PTH promotes the differentiation of MSCs into osteoblasts. Hence, our objective in the proposed study is to determine the effect of injection of MSCs combined with PTH therapy on bone regeneration in a multiple vertebral bone defect model in osteoporotic rats. The optimal doses of PTH and numbers of MSCs per injection also will be determined. Human bone marrow-derived MSCs will be injected into osteoporotic athymic rats with multiple lumbar vertebral bone defects. MSC homing to bone defects will be monitored using micro- and molecular imaging. Subsequent studies will test increasing dosages of PTH to define the optimal dose for maximal enhancement of MSC homing to a fracture. Bone regeneration will be monitored using micro–CT imaging and biomechanical analyses (to determine structural integrity of newly repaired bone). Subsequent studies will determine whether increasing the number of injected MSCs linearly enhances bone tissue formation. These studies will aid in the creation of an evidence base for future clinical trials that could revolutionize the treatment of vertebral fractures and other complex fractures in patients suffering from osteoporosis.
Statement of Benefit to California: 
Approximately 10 million people in the United States are diagnosed as osteoporotic, while an additional 34 million are classified as having low bone mass. The lifetime incidence of fragility fractures secondary to osteoporosis in females over fifty years of age is approximately 1 in 2, and in males over the age of fifty, is 1 in 4. Osteoporosis-related vertebral compression fractures (OVCFs) are the most common fragility fractures in the United States, accounting for approximately 700,000 injuries per year, twice the rate of hip fractures. Approximately 70,000 OVCFs result in hospitalization each year with an average hospital stay per patient of 8 days. Fragility fractures due to osteoporosis also place a severe financial strain upon the health care industry. Estimates show there were approximately 1.5 million osteoporosis-related fractures in the United States in 2001, the care of which cost about $17 billion. Moreover, as the number of individuals over the age of fifty continues to increase, costs are predicted to rise to an estimated $60 billion a year by the year 2030. OVCFs have previously received limited attention from the spine care community. This oversight may be a result of the perception that OVCFs are benign, self-limited problems or that treatment options are limited. However, it has become clear that OVCFs are associated with significant physiologic and functional impairment, even in patients not presenting for medical evaluation at the time of fracture. Current treatment of osteoporotic patients is mostly focused on prevention of OVCFs. There are a few options of treatment when OVCFs actually occur. Since open surgery involves morbidity and implant failure in the osteoporotic patient population, nonoperative management, including medications and bracing, is usually recommended for the vast majority of patients. Unfortunately, large numbers of patients report intractable pain and inability to return to activities. Currently there is no efficient biological solution for the treatment of OVCFs. The proposed study will further develop a biological therapeutic solution that will accelerate repair of OVCFs. The treatment will rely upon a combination of drug and adult stem cell therapy; both are either approved for clinical use or in clinical trials. It will also involve a simple intravenous injection instead of a percutaneous injection of a polymer, which does not restore lost bone tissue. Data generated form this study could potentially revolutionize the treatment of vertebral fractures and other complex fractures in patients suffering from osteoporosis, and so benefit the citizens of California by reducing hospitalization periods, operative costs and loss of workdays, and by improving quality of life for Californians with osteoporosis that are at risk for OVCFs.
Progress Report: 
  • The goal of the proposed study is to develop a treatment for accelerating multiple vertebral fracture repairs. Approximately 10 million people in the United States are diagnosed as osteoporotic, while an additional 34 million are classified as having low bone mass. The lifetime incidence of fragility fractures secondary to osteoporosis in females over the age of fifty years of age is approximately 1 in 2, and in males over the age of fifty, is 1 in 4. Vertebral compression fractures (VCFs) are the most common fragility fractures in the United States, accounting for approximately 700,000 injuries per year, twice the rate of hip fractures. Approximately 70,000 VCFs result in hospitalization each year with an average hospital stay per patient of 8 days. Current treatment of osteoporotic patients is mostly focused on prevention of VCFs mainly using new medicines such as Alendronate and Parathyroid Hormone (1-34). But there are a few options of treatment when VCFs actually occur. New, non-biological, methods have been developed to regain the biomechanical properties of a fractured vertebral body. These methods include the minimally invasive procedures of vertebroplasty and balloon tamp reduction. Both procedures involve injection of synthetic nonbiological material that does not resorb and instead remains a permanent foreign-body fixture in the spine. Ultimately, a biological solution that would promote rapid fracture healing and stimulate normal bone production would be the best for osteoporotic patients with vertebral column injuries. Our pilot studies have shown that bone fractures can be treated by intravenous administration of adult stem cells combined with a dose of parathyroid hormone, which is approved by the FDA for use as an anabolic agent in the treatment of severe osteoporosis. Therefore, in the proposed project we will determine the ability of injected stem cells to migrate to a vertebral fracture site. We will also analyze the combined effect of PTH and stem cells on vertebral fracture repair.
  • The goal of the study is to develop a treatment for accelerating multiple vertebral fracture repair. Approximately 10 million people in the United States are diagnosed as osteoporotic, while an additional 34 million are classified as having low bone mass. Vertebral compression fractures (VCFs) are the most common fractures in the United States, accounting for approximately 700,000 injuries per year, twice the rate of hip fractures. Approximately 70,000 VCFs result in hospitalization each year with an average hospital stay per patient of 8 days. Current treatment of osteoporotic patients is mostly focused on prevention of VCFs mainly using new medicines such as Alendronate and Parathyroid Hormone (PTH). But there are no options of treatment when VCFs actually occur either than bed rest and pain medication.
  • Our goal is to induce efficient vertebral fracture repair by a combined treatment of adult stem cells and PTH. During the last year we treated osteoporotic animals (rodents) with human stem cells, isolated from bone marrow. The cells were injected to the blood circulation followed by PTH treatment for three weeks. In order to evaluate whether the injected cells migrated to the region of the spinal fractures, we used fluorescent cells. Using a highly sensitive camera we were able to track the injected cells in the body of the animals over 55 days. Our results showed that more cells targeted the spine region when PTH was given to the animals compared to a control group that did not receive PTH. In addition, we analyzed the effect of the stem cell treatment on the repair of spinal fractures. Using high resolution CT imaging we found that osteoporotic animals treated with stem cells and PTH had significantly more bone fracture repair when compared to untreated animals and to animals treated with PTH or stem cells only.
  • In conclusion, we have generated promising results demonstrating the efficiency of stem cell therapy combined with PTH for the treatment of vertebral fractures. We will further explore this effect in the 3rd year of the project, aiming to promote this therapy further towards clinical use.
  • During the 3rd year of the project we have been able to show that when stem cells are injected to osteoporotic animals, they migrate and home to vertebral fractures. We also showed that treating the animals with an FDA-approved drug, PTH, enhances the homing of the stem cells (i.e. more cells migrate to the site of the fracture). Using microscopy and specific fluorescent dyes we were able to investigate the fate of the injected stem cells after they arrived to the fracture site. Apparently these cells turn into bone-forming cells and participate in the fracture repair. Indeed, when we measured the repair of the vertebral fractures (i.e. amount of new bone that was formed) we found that the combination therapy of stem cells and PTH had a superior effect compared to the therapies that included only stem cells or were left untreated. We are currently evaluating the use of lower doses of PTH that are equivalent to the dose used for prevention of fractures in osteoporosis patients. In summary, we believe that our results so far merit further investigation of the proposed therapy that might prove beneficial of numerous patients suffering from vertebral compression fractures every year.

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