Funding opportunities

Clinical Regenerative Wound Healing With Stem Cells

Funding Type: 
Disease Team Planning
Grant Number: 
DT1-00653
Principle Investigator: 
Funds requested: 
$42 574
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Chronic skin wounds affect a large number of patients every year who suffer from diabetes, burns, venous disease leg ulcers, arterial disease leg ulcers, pressure ulcers, and ulcers from spinal diseases. The annual health care costs for wound care in the United States is $15 billion. The purpose of our CIRM Disease Team Planning Award Proposal is to create an investigative team across the academic departments of Pathology, Dermatology, Surgery, Dermatology and Cell and Neurobiology who will work together using stem cell technology to study regenerative wound healing of the skin in which there is restoration of the skin’s normal architecture, lack of fibrosis and regeneration of skin appendages – hair follicles, sebaceous glands and eccrine glands. This type of healing takes place in Nature such as the regeneration of the limb of a newt, but does not occur normally in post-natal human beings. Our team consists of (i) a NIH-funded Plastic Surgeon who runs the {REDACTED} Burn Unit and has performed many wound healing clinical trials; (ii) a NIH-funded Pathologist with expertise in epidermal-mesenchymal interactions and skin appendage formation; (iii) an accomplished stem cell biologist; (iv) a NIH-funded clinical investigator dermatologist with expertise in wound healing and (iv) two NIH-funded molecular biologists with expertise in gene therapy, lentiviral delivery of genes into human skin cells, skin cell motility and wound healing. In this proposal, the team will organize a research agenda that is disease oriented with the goal to translate our findings to the clinic and manipulate the microenvironment of human skin wounds such that they heal in with a regenerative, non-scarring process in which there is an organized expression of skin appendages in the healed skin using stem cells. If successful, this would completely alter the wound healing landscape and have a major impact on the care of burn wounds, chronic leg ulcers from patients with venous and arterial disease, pressure ulcers and spinal cord injury-induced wounds. It would also benefit children who are born with a genetic scarring blistering disease of the skin called dystrophic epidermolysis bullosa for which there is currently no cure or treatment and which is usually fatal during young adulthood. In this Planning Grant, we will have Team Meetings every 2 weeks, 2 week-end planning Retreats and 2 consultants {REDACTED}
Statement of Benefit to California: 
Wound healing of skin wounds is a major public health problem. It is estimated that approximately $15 billion dollars per annum are expended for the diagnosis and treatment of skin wounds from pressure ulcers, spinal cord injuries, diabetes, venous disease, arterial disease, and surgery. To date, skin wounds heal, but they do not regenerate normal human skin. Rather, they heal as a facsimile of normal skin with a fibrosed (scarred dermis), effaced epidermis and an organ lacking sweat glands, oil glands and hair. This facsimile of normal skin has considerable morbidity, lacks critical skin functions and his highly vulnerable to further injury and morbidity. The fibrosis of large burn wound across limbs and body parts induces contractures that can limit the mobility and functionality of the victim. Similar problems occur in genetic skin diseases such as dystrophic epidermolysis bullosa (DEB) which is a widespread blistering and scarring disease of children who develop such fibrotic “mitten” deformities of their hands to render their hands functionally useless. The translational research of this project would have a major impact of the health of citizens of California and the World.
Review Summary: 
Executive Summary This proposal is aimed at developing a collaborative approach for the application of stem cell-based therapy to regenerative wound healing of the skin. Therapies will be targeted to the repair of burn wounds, chronic skin ulcers, pressure ulcers, and skin damage from dystrophic epidermolysis bullosa, an inherited skin disorder in children. The proposed team will be composed of experts in the biology and pathology of skin, and include clinicians, stem cell biologists, and molecular biologists. Planning activities will be focused on meetings and retreats at which the team will concentrate on organizing the research agenda and accessing outside experts of skin stem cells. This is a well organized proposal to develop stem cell-based therapies for the treatment of chronic skin wounds. The applicant outlines a beneficial collaboration between basic scientists and clinical dermatologists to devise an ordered and promising disease team approach. The proposal is focused on common and important clinical problems associated with both injury and disease of the skin. The skin is an obvious and appropriate target for stem cell therapy given its immediate accessibility for diagnosis, treatment, and monitoring. The rationale for the approach is well established. One concern is that it is unclear which types of stem cells or progenitor cells will be most applicable for the proposed therapeutic approaches. A second concern is the current absence of useful animal models for preclinical evaluation of proposed therapies. It is anticipated that these concerns will be addressed in a subsequent disease team proposal. The PI is a senior clinical dermatologist who is a leader in the field of epithelial biology. He/she has published significant papers on wound healing, epidermolysis bullosa, and other topics related to the proposal. He/she has conducted clinical trials in wound healing and possesses ample experience in leading collaborative research teams. The PI is an excellent and experienced leader for the project and represents a major strength of the proposal. The proposal clearly outlines the composition of the disease team and the expected roles for each member. The team includes appropriate and well qualified basic scientists and clinical investigators. Although two experts in skin stem cells will be consulted during the planning process, the disease team could benefit from the addition of such an expert as a full participant in the project. The described planning process should yield a cohesive team approach for developing an effective and beneficial disease team proposal. Reviewer Synopsis This proposal deals with the use of stem cell technology in regenerative wound healing of the skin. The research is targeted at significant and important clinical conditions, the repair of burn wounds, chronic skin ulcers, pressure ulcers and an inherited skin disease in children, dystrophic epidermolysis bullosa. The proposal is to bring a group of experts in the biology and pathology of skin as well as clinical dermatologists and stem cell experts in their institution, to devise strategies to restore all aspects of the skin’s architecture in the diseases noted above. They plan a series of meetings and retreats along with consultation with two outside consultants who they regard as the “fathers of skin stem cells.” Reviewer One Comments Concept: • Target: The concept is to use genetically engineered human ESCs to generate fully functional skin for regenerative wound healing in burn wounds, ulcers and dystrophic epidermolysis bullosa. • Evidence / maturity: The use of stem cells in the proposed concept is not sufficiently justified, given the success by the PI and co-investigators on using molecular approaches and other cellular approaches. The feasibility to transfect hESCs has not been demonstrated either. It remains unclear that a genetically engineered hESC-based approach will be ready for clinical studies within 5 years. Principal Investigator: PI has ample experience in leading multiple investigator teams. He has been leading basic research and clinical trials. He is well suited to lead this team and the development of a research plan for a Disease Team Award. Planning Approach: • The expertise is skewed towards dermatology, pathology, surgery, and cell biology. Given that most critical unanswered questions lie with hESC manipulation, the team should consider further strengthen hESC expertise. • Planning process for preparing the potential Disease Team to complete the Research Award is moderately discussed. Remaining to be discussed is the how to focus the research effort in preparing for clinical trials in 5 years. Reviewer Two Comments Concept: This proposal targets wound healing. The concept is to use stem cells to regenerate skin with normal architecture, non-scarring process with an organized expression of skin appendages (equivalent to newt limb regeneration). Good for healed skin wounds such as burns, ulcers, children with DEB (termed as regenerative wound healing). Envision three parts: • Create iPS from dermal fibroblasts and characterize them. • Discover how to manipulate conditions to create properly differentiated epithelium, functional glands, and hair appendages. • Determine how best to deliver cells to patients. Strengths: • PI has already assembled a local group of experts with diverse research interests that appear to have possible applications to wound healing. This group includes clinicians and molecular biologists. • PI has proven track record in conducting clinical trials in wound healing. • Dr. Chen holds patents on the use of Collagen VII for accelerating wound closure. Weaknesses: • PI himself does not appear to have significant familiarity with stem cells. However, he has recruited two consultants who are described as founders of skin stem cell biology, along with other team members. • It is not clear how well the various team members expertise will come together to solve the gaps in moving this concept into clinical trial. • There is no evidence of useful animal models, except perhaps for DEB. • Gene delivery to force stem cell differentiation has many pitfalls, including safety concerns with proposed approach for clinical use, and questions about reliability and reproducibility of this approach. Principal Investigator: PI: Dr. Woodley is Professor and Chair of Dermatology at USC for 10 years. He has significant publications and is well funded from NIH in disease areas associated with this proposal, and in dermal fibroblasts. Planning Approach: Planning Approach: • Team meeting every two weeks • 2 weekend retreats • Advice from consultants • Two fathers of Skin Stem Cells will “visit” during 6 month planning process. • Biostatistician and epidemiologist consultant • Planning of clinical study • Two team members go to DC to meet with FDA and Orphan Disease Program Reviewer Three Comments Concept: It is clear that the diseases and skin injuries that they propose to target are common and important clinical problems. Stem cell therapies that could successfully treat such conditions would be regarded as a major success for stem cells in tissue repair. They make the case that the collaboration between their team members who include basic scientists and clinical dermatologists is a prerequisite for the research to be successful and be taken into the clinic. Their concept is that they will isolate stem cells that are engineered to produce all the cellular constituents of normal skin with differentiated epidermis. This they describe as “regenerative wound healing” which differs from the way normal skin heals. What is not entirely clear from the proposal is what stem cells they would use. They mention isolating stem cells from the hair follicle bulge of normal human skin. They also mention preparing stem cells from human skin fibroblasts using new technology – I assume they mean iPS cells, but there is a lack of clarity here. They do however note that isolation and characterization of the required stem cells will be the goal of their first specific aim if they are funded. Principal Investigator: The principal investigator is a senior clinical dermatologist, the Chair of Dermatology at USC and a leader in his discipline. He has three R01s and a VA grant as well as being Co-PI on another NIH grant. He is clearly well qualified to lead this group and take this research into the clinic. He has assembled a well qualified team at USC who hold complementary expertise. This application was one of the few that specifically addressed the Application Instructions in the Disease Team Planning Award RFA. Planning Approach: The applicant describes well how the team was assembled and how the individual responsibilities of each team member will play in the planning process and if funded, in the second phase of the Disease Team Award. They propose a series of meetings, with visits from their consultants and visits to the FDA etc. These seem well planned and these plans should lead to a cohesive team approach. Reviewer Four Comments Concept: This proposal involves extending findings from the study of a rare genetic disorder, recessive dystrophic epidermolysis bullosa (RDEB) to a more common clinical problem, that of healing of chronic wounds. This proposal deals with the use of human embryonic stem cells to repopulate a chronic wound and regenerate functional tissue, including appendages, and to minimize dermal scarring. This concept is termed “regenerative wound healing”. The questions that this proposal must address are 1) Why do chronic wounds fail to recruit stem cells? 2) Why are chronic wounds inhospitable environments for stem cells? and 3) Are the same processes that govern hair regeneration vs scar formation (dkk promoting scar vs wnt promoting hair) active in chronic wounds. Principal Investigator: The PI has a long and strong track record in epithelial biology. He has set up collaborative groups previously as chairman at Northwestern and now at USC. He has shown that genetic deficiency of type 7 collagen can be corrected by recombinant collagen 7 or by fibroblasts that secrete type 7 collagen. While his major work is not stem cell biology, he has recruited appropriate collaborators at USC to assist this work Planning Approach: Space limitations prevent a full assessment of detail of this proposal. The PI has an extensive history of the study of factors relevant to wound healing, such as type 7 collagen and epidermal chemotaxis. He has recruited appropriate collaborators in terms of appendages (Dr Chuong), molecular biology (Dr Chen), stem cell biologists (Drs Pera and Kobeilak), clinical wound healing (Dr Garner). The proposal lacks detail on how to assess which cytokines prevent optimal stem cell take in the wound, and may be due to aberrant dkk/wnt, but the proposal limits the amount of detail that can be demonstrated
Conflicts: 

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