Stem Cells for Treating Pre-Arthritic Focal Cartilage Defects

Funding Type: 
Disease Team Research I
Grant Number: 
DR1-01454
ICOC Funds Committed: 
$0
Disease Focus: 
Skin Disease
Pediatrics
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
Public Abstract: 
Arthritis is a disabling condition that afflicts 6 million Californians and costs our state nearly $32 billion a year for health care and lost wages. Yet arthritis remains an unmet medical need and its overall impact will increase steadily given that more of the population is aging and that the inability to maintain an active lifestyle has severe consequences for many aspects of health. Sixty million Americans are projected to have arthritis by 2020. In the absence of effective 'arthritis drugs', joint replacements offer some relief but have limited durability and are unsuitable for young patients. Other treatments that try to repair cartilage damaged prior to arthritis, such as microfracture of underlying bone or cartilage cell transplantation, fail to restore native mechanical and biological properties of the joint and do not avoid disease progression. For preventing arthritis, stem cells have obvious appeal, but directing them to synthesize a desirable cartilage matrix has proven challenging. We have made a fundamental advance in overcoming limitations to the use of stem cells for cartilage repair. We have developed a Product in which human mesenchymal stem cells (MSC) are grown alongside highly instructive juvenile cartilage cells. These cells are arranged in bilaminar cell pellets (BCPs), and embedded in a mechanically functional biomaterial composite. BCPs synthesize abundant articular cartilage matrix, adapt to the unique environment of the joint, and resist inflammation. The biomaterial composite retains the BCPs at the defect site and supports joint forces. Over time BCPs will secrete cartilage matrix and replace the biomaterials. We propose a focused plan to optimize the cell source and BCP interactions with biomaterials; establish cell banks; demonstrate feasibility, safety, and efficacy; and develop clinical trial and commercialization plans. Our goal is to accelerate translation of this novel stem cell-based therapy to provide an early intervention for preventing and treating arthritis. With support of a CIRM Disease Team Planning Grant, we assembled an outstanding team of experts from Academia and Industry with the experience and motivation to achieve our goal. The team leader is Director of an industry-collaborative center and an Orthopaedic Biomechanics Laboratory, and a pioneer of protocols for turning stem cells into cartilage. Our Academic partners bring world-recognized leadership in stem cell and skeletal biology, and clinical expertise in orthopaedic surgery, including past clinical evaluations of other cell-based therapies. Our Industry partners have established products for clinical applications, and contribute expertise in cell sourcing, biomaterials, manufacturing, and regulatory processes. By combining the creativity and innovation of Academia with the pragmatic focus of Industry, our team is poised to meet the challenge of filing an IND within 4 years for a stem cell-based therapy for cartilage regeneration.
Statement of Benefit to California: 
Approximately 6 million adults in California, or 27% of the population have some form of arthritis. This disease costs California nearly $32 billion each year, with an estimated $23.2 billion spent on direct medical care and $8.3 billion due to lost wages. The centers for Disease Control and Prevention projects that 60 million people nationwide will have arthritis by 2020. Osteoarthritis is a disabling disease that limits the ability to engage in the regular physical activity that prevents obesity, diabetes, and cardiovascular disease. Consequently, successful development of improved arthritis therapies will benefit a significant portion of the California population. Additionally, we anticipate that the management structure of this program along with the cell/matrix technologies can ultimately be applied to a host of other musculoskeletal diseases such as back pain, osteoporosis, and fracture repair. In addition to the health of Californians, cell based therapies for arthritis and other musculoskeletal conditions provide a huge commercial opportunity for California industry. Credit Suisse has estimated that the growth potential for the orthopaedic industry focused on hip and knee treatment is positive, with projected global sales expanding from $9.6 billion in 2006 to $13 billion in 2011. The orthobiologic market that includes regenerative technologies currently accounts for roughly 12% of the worldwide orthopaedic implant market and is the fastest growing segment, at 20% annually. Our Team partners with several California companies who will directly benefit from this effort. Clearly their economic success will provide employment opportunities for Californians, tax revenue for the state, and help maintain California as a world leader in biotechnology research and development. This work also aids the research enterprise of California universities by augmenting our competitiveness for NIH funding. This, in turn, brings the brightest scientific talent to the state, fuels innovation, and ensures continued California leadership in the biotech industry. Given the significant unmet clinical need, market opportunity, and rapidly evolving technologies, we anticipate that stem-cell based therapies for arthritis will be realized in the next 4 to 8 years. The CIRM Disease Team Award can assure that this important therapy with the potential to prevent the progression of osteoarthritis is developed in California.
Progress Report: 
  • Genetic skin diseases constitute a diverse group of several hundred diseases that affect up to 2% of the population and include common disease such as psoriasis, atopic dermatitis, and wound healing. Patients with one genetic disease, dystrophic Epidermolysis bullosa (EB), lack a normal collagen VII (COL7A1) gene and suffer from debilitating blistering which leads to chronic wounds and scarring that can be lethal by young adulthood. The disease is devastating and despite all efforts, current therapy for DEB is limited to wound care. For recessive dystrophic EB (RDEB) where there is no COL7A1 protein, our EB Disease team has shown that retroviral delivery of the COL7A1 using gene transfer provides a powerful disease modifying activity as autologous, cell-based therapy. In this process, the patient' own cells can be induced to make normal collagen VII. The patients can then receive their own corrected cells back onto their skin. While successful, our initial approach cannot treat many dominantly inherited diseases such as dominant dystrophic EB (DDEB) where a poison subunit inhibits the function of the normal protein. Recent development of induced pluripotent stem (iPS) cells that are generated from the somatic cells of individual patients could provide an ideal source of therapy. Because of recent advances by our team and others in stem cell technology, our hypothesis is that we can create genetically corrected iPS cells for dominant skin diseases such as DDEB as well as recessive diseases such as RDEB. The goal of the EB Disease team is to develop iPS cells of patients with DEB and genetically correct the patient's own collagen VII defect. We then plan to convert the iPS cell back into skin cells that can be grafted onto the patient's wounds. We plan to develop the processes necessary for iPS cell generation, genetic correction and development of a product that can be grafted back onto the patient's own skin. We will be working within the Food and Drug Administration (FDA) in order to create this process while meeting the requirement for successful drug development. Among the FDA requirements are Good Manufacturing Practice (GMP) documenting the purity of the created drug.
  • We have made significant scientific progress during the first year of this grant. Using GMP methods we have developed the initial tools required for successful iPS cell development which will meet the FDA requirements for drug development. We have generated iPS cell lines from subjects with documented DEB and began the processes necessary for genetic correction and future skin grafting of the corrected cells back onto the patient. We are doing extensive testing of the iPS-derived skin cells using human skin tissue models to ensure the safety and efficacy of these cells. Soon we will work together with the FDA and our collaborators to generate patient-specific skin grafts. The ability to therapeutically reprogram and replace diseased skin would allow this procedure to develop therapeutic reprogramming approaches for a variety of both common and life-threatening skin diseases. Moreover, genetically-corrected pluripotent iPS cells could form the basis of future systemic therapies to other organs besides the skin to treat common genetic disorders.
  • Genetic skin diseases constitute a diverse group of several hundred diseases that affect up to 2% of the population and include common disease such as psoriasis, atopic dermatitis, and wound healing. Patients with one genetic disease, dystrophic epidermolysis bullosa (DEB), lack a normal collagen VII (COL7A1) gene and suffer from debilitating blistering which leads to chronic wounds and scarring that can be lethal by young adulthood. The disease is devastating and despite all efforts, current therapy for DEB is limited to wound care. For recessive dystrophic EB (RDEB) where there is no COL7A1 protein, our EB Disease team has shown that retroviral delivery of the COL7A1 using gene transfer provides a powerful disease modifying activity as autologous, cell-based therapy. In this process, the patient's own cells can be induced to make normal collagen VII. The patients can then receive their own corrected cells back onto their skin. While successful, our initial approach cannot treat many dominantly inherited diseases such as dominant dystrophic EB (DDEB) where a poison subunit inhibits the function of the normal protein. Recent development of induced pluripotent stem (iPS) cells that are generated from the somatic cells of individual patients could provide an ideal source of therapy. Because of recent advances by our team and others in stem cell technology, our hypothesis is that we can create genetically corrected iPS cells for dominant skin diseases such as DDEB as well as recessive diseases such as RDEB. The goal of the EB Disease team is to develop iPS cells of patients with DEB and genetically correct the patient's own collagen VII defect. We then plan to convert the iPS cell back into skin cells that can be grafted onto the patient's wounds. We plan to develop the processes necessary for iPS cell generation, genetic correction and development of a product that can be grafted back onto the patient's own skin. We will be working with the Food and Drug Administration (FDA) in order to create this process while meeting the requirement for successful drug development. Among the FDA requirements are Good Manufacturing Practice (GMP), documenting the purity of the created drug. We have made significant scientific progress during the first two years of this grant. We have developed the initial tools required for successful iPS cell development which will meet the FDA requirements for drug development. We have generated iPS cell lines from subjects with documented DEB, identified the genetic mutations, and commenced work on the correction of several mutations in the iPS Cells. We are developing the process necessary for future skin grafting of the corrected cells back onto the patient, and have already successfully generated the initial GMP manufacturing protocols leading to clinical grade, corrected patient skin cells. We are currently doing extensive testing of the iPS-derived skin cells using human skin tissue models to ensure the safety and efficacy of these cells. Soon we will work together with the FDA and our collaborators to generate patient-specific skin grafts. The ability to therapeutically reprogram and replace diseased skin would allow this procedure to develop therapeutic reprogramming approaches for a variety of both common and life-threatening skin diseases. Moreover, genetically-corrected pluripotent iPS cells could form the basis of future systemic therapies to other organs besides the skin to treat common genetic disorders.
  • Genetic skin diseases constitute a diverse group of several hundred diseases that affect up to 2% of the population and include common disease such as psoriasis, atopic dermatitis, and wound healing. Patients with one genetic disease, dystrophic epidermolysis bullosa (DEB), lack a normal collagen VII (COL7A1) gene and suffer from debilitating blistering which leads to chronic wounds and scarring that can be lethal by young adulthood. The disease is devastating and despite all efforts, current therapy for DEB is limited to wound care. For recessive dystrophic EB (RDEB) where there is no effective COL7A1 protein, our EB Disease team has shown that retroviral delivery of the COL7A1 using gene transfer provides a powerful disease modifying activity as autologous, cell-based therapy. In this process, the patient' own cells can be induced to make normal collagen VII. The patients can then receive their own corrected cells back onto their skin. While successful, our initial approach cannot treat many dominantly inherited diseases such as dominant dystrophic EB (DDEB) where a genetically abnormal poison subunit inhibits the function of the normal protein. Recent development of induced pluripotent stem (iPS) cells that are generated from the somatic cells of individual patients could provide an ideal source of therapy. Because of recent advances by our team and others in stem cell technology, our hypothesis is that we can create genetically corrected iPS cells for dominant skin diseases such as DDEB as well as recessive diseases such as RDEB. The goal of the EB Disease team is to develop iPS cells of patients with DEB and genetically correct the patient's own collagen VII defect. We then plan to convert the iPS cells back into skin cells that can be grafted onto the patient's wounds. We plan to develop the processes necessary for iPS cell generation, genetic correction and development of a product that can be grafted back onto the patient's own skin. We are working within the Food and Drug Administration (FDA) in order to create this process while meeting the requirement for successful drug development. Among the FDA requirements are Good Manufacturing Practice (GMP) documenting the purity of the created drug. We have made significant scientific progress during the first three years of this grant. We have developed the initial tools required for successful iPS cell development which will meet the FDA requirements for drug development. We have generated iPS cell lines from subjects with documented DEB. In addition, we have identified the genetic mutations in the iPS cells and corrected several mutations. We are developing the process necessary for future skin grafting of the corrected cells back onto the patient and have already successfully generated the initial GMP manufacturing protocols leading to clinical grade, corrected patient skin cells. We are currently doing extensive testing of the iPS-derived skin cells using human skin tissue models to ensure the safety and efficacy of these cells. The ability to therapeutically reprogram and replace diseased skin would allow this procedure to develop therapeutic reprogramming approaches for a variety of both common and life-threatening skin diseases. Moreover, genetically-corrected pluripotent iPS cells could form the basis of future systemic therapies to other organs besides the skin to treat common genetic disorders.

© 2013 California Institute for Regenerative Medicine