This study addresses the cartilage defects resulting from injuries or from wear-and-tear that can eventually degenerate to osteoarthritis. This is a significant problem that impacts millions and costs in excess of $65B per annum in the US alone. Addressing this indication successfully holds potential for halting the progression of cartilage damage before it destroys the entire joint. We have shown that articular cartilage can be engineered with properties on par with native tissues using chondrocytes. Also, skin derived stem cells can be used to engineer new cartilage with significant mechanical integrity. Combining these findings, the new cellular therapy that this proposal seeks to develop is an autologous skin cell-derived combination product for articular cartilage repair. Three aims are proposed to advance this autologous, adult stem cell-based method: First, protocols shown to be efficacious in cartilage tissue engineering will be applied to skin-derived stem cells and show safety in the mouse model. Then, using a preclinical model, the desired biological response, toxicology, and durability will be verified. Finally, short-term safety and efficacy of cartilage repair will be examined in a different preclinical model. Successful completion of this DCF project will allow the start of preclinical studies in the sheep that demonstrate long-term safety and efficacy, as specified by the FDA.
Arthritis is the leading cause of disability in the US, affecting over 46 million Americans. Of these, over 5 million Californians are affected by this debilitating disease, with roughly 3 million that are women and over 2 million that are men. Additionally, Californian youth is also included in the estimated 30 million children who participate in organized sports activities, whose yearly costs for injuries have been projected to be $1.8 billion. For young patients with knee injuries, 75% exhibit superficial (grade I–II) and 25% exhibit deep (grade III–IV) cartilage lesions. Young patients not only need to retain mobility for many years in life but also new, tissue-sparing techniques. This proposal seeks to develop an autologous, adult stem cell-based therapy that addresses grade II-IV cartilage lesions. The source of these cells will be the skin, using minimally invasive procedures. The development of such a therapy would expand the clinical options available to Californians. The assembled team of academics, orthopaedic surgeons, and veterinary surgeons are based in the [REDACTED]. The refinement of this research will not only benefit [REDACTED] in terms of increasing competitiveness for NIH funding, but it will also allow for Californian companies to license the technology and therefore benefit economically.
This Development Candidate Feasibility project is intended to develop autologous engineered cartilage to treat focal cartilage defects which can lead to osteoarthritis. The project will first adapt a cartilage engineering strategy to utilize autologous skin-derived stem cells. The project will then perform pre-clinical studies in both small and large animal models to show safety and proof of concept for the engineered cartilage to treat damaged cartilage.
Objective and Milestones
- The Target Product Profile is appropriate and feasible.
- Milestones and timeline are clear and realistic.
Rationale and Significance
- The rationale for the experimental approach combining a skin-derived cell source and tissue engineering is logical and compelling. The cell source itself could be a major advance for ease of biopsy.
-The tissue engineering approach employed was praised for its novelty.
- Osteochondral lesions are a serious unmet medical need.
Research Project Feasibility and Design
- The preliminary data are encouraging. The applicant shows clear evidence that these cells have a strong potential to undergo chondrogenesis.
- The team has all the necessary in vitro methods and preclinical models to undertake the work proposed.
- The project is well designed with consideration paid to meeting regulatory requirements.
- Good outcome measures and a functional index are proposed.
- Reviewers suggested large animal studies should be conducted using an autologous control, rather than the proposed allogeneic control to ensure an appropriate comparator.
- Reviewers also expressed minor concerns regarding the need for more details about the novel cell source.
Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team
- The PI has a strong track record of success in tissue engineering as well as experience in the commercial sector.
- Team has all appropriate expertise.
Collaborations, Assets, Resources and Environment
- Proposed budget is appropriate.
- Appropriate resources are in place.
Responsiveness to the RFA
- No relevant concerns were highlighted by reviewers under this review criterion.