Disease Team Therapy Development - Research
The primary goal is to bring a safe and effective therapy to children with severe large airway disease. Our intent is to implement all of the necessary steps for a successful new stem/progenitor cell-derived airway transplant for clinical trials in children within 4 years. Our team builds on first-in-human surgical successes with stem cell-based tissue engineered airway implants in compassionate use cases in a young adult and in a child. To this end, we will perform the necessary preclinical studies to support a successful FDA IND application within 3 years. We propose to use stem/progenitor cells from the patient to treat an extraordinarily difficult to manage health problem in children, namely large airway disease. In children this leads to collapse of tracheal cartilage causing severe airway obstruction that is life-threatening. It occurs in approximately 200 children in California each year and the morbidity and mortality associated with this disease are very high. Approximately 25% of these young patients die if not successfully treated. Treatment costs for these children are very high, and the familial and societal investments are substantially higher, although outcomes are consistently poor. The endpoint desired is normal airway and lung function and an improved quality of life. Our team aims to eliminate the need for repeated surgical interventions which are not necessarily successful, presently the standard of care for children with large airway obstruction. Bioengineered airway transplants that use the cells of the patients could be used in humans of all age groups and would not require lifelong harmful anti-rejection medications. In 2008/2010, we used stem cell-based, engineered tracheal implants to successfully save a young woman's and a child's life. The child has now returned to school and has grown 4 inches in a year. These first-in-human studies emphasize that our goal is realistic and paves the way for clinical trials in children after carefully designed safety studies. Stem/progenitor cell-derived airway transplants that use the patients' cells have the clinical advantage of not requiring anti-rejection medications. Our experience, to date, indicates such medication is not needed and this finding represents a scientific and clinical breakthrough in organ transplantation. While clear medical benefit was demonstrated in these two preliminary patients, there is substantial work that must be done before such transplants can be considered routine for pediatric and adult patients. We address this challenge with our team approach and emphasize the synergism that occurs when linking team members with expertise in a variety of scientific and medical disciplines to address this critical need. This new therapeutic approach could offer a tremendous benefit to children and patients in other age groups who are in desperate need of new treatment options.
Statement of Benefit to California:
The citizens of California have generously invested in stem cell research and a return on their investment will include breakthroughs in medical treatments for diseases where there are currently limited options. Stem/progenitor cell-derived airway transplantation is a leading example of translational research in regenerative medicine that can be used for a host of diseases. Through this team effort scientists and physicians will lead the early promise of airway transplantation to clinical trials in California and beyond. This research team proposes to use stem and progenitor cells to cure an extraordinarily difficult to manage and life-threatening health problem in children. Severe airway obstruction occurs in approximately 200 children in California each year. The morbidity and mortality associated with this disease is very high; approximately 25% of patients will die if not successfully treated. The knowledge gained from the tissue engineering and preclinical studies proposed will provide a new technology that can be applied to other disorders in California. We foresee that our stem cell-derived airway transplant could also be applied to treat an important subpopulation of adults with severe chronic obstructive pulmonary disease (COPD) and the large number of children and adults with severe subglottic stenoses that have proven refractory to standard surgical interventions, and patients with debilitating laryngeal scarring. Given that the prevalence rate of COPD for California citizens greater than 65 years of age approaches 10%, if even 0.1% of COPD patients in California were candidates, specifically those with associated tracheobronchomalacia, then greater than 3,000 patients might benefit from this treatment. The methods and technology developed from this project can also be used as the basis for other similar health needs including esophageal, bladder, and bowel replacements for disorders where present treatments are very limited and impair quality of life.
This proposal focuses on the preclinical and initial clinical development of an engineered stem-cell based airway transplant for children with large airway disease. The proposed approach utilizes a biological scaffold with two different autologous cell types, and builds on experience with two first-in-human compassionate use cases. The applicant proposes to optimize production and characterization of the therapeutic candidate and to conduct preclinical studies including IND-enabling studies within the first three years of the project. During the fourth and final year of the project the applicant proposes to conduct a Phase 1 clinical trial in severe pediatric cases. The applicant states that the first trial would provide information on safety and efficacy, as well as allow refinement of technical aspects of the procedure and outcome measures. Data from this trial would inform future clinical trials, including early clinical studies in additional clinical settings. Significance and Impact - The panel characterized this proposal as a high risk / high reward project. In certain clinical scenarios proposed, the proposed treatment could be curative; however, failure could be catastrophic to the patients. - Several reviewers judged that the magnitude of the problem (i.e. the cases for which this treatment is clinically applicable) was overstated in the application. Some cases could be treated satisfactorily with alternative surgical approaches. - Initial results have been achieved in two human cases in which the PI has been involved. - The project is important for the field as a demonstration of bioengineering concepts. Project Rationale - At this early stage of technology development, the choice of the pediatric patient population was not justified. The panel felt strongly that a staged development plan first in adults would be more appropriate. - The panel acknowledged the proof-of-concept data in two patient cases as demonstration that the technique could work. - The applicants present preclinical data justifying the use of each of the candidate components, both the scaffold and cells. Therapeutic Development Readiness - Preclinical data in the application demonstrates feasibility of the approach in a large animal model. - Adjustment of the transplanted construct to the growth of the patient, a key safety parameter for growing pediatric patients, has not yet been demonstrated preclinically. However, a key experiment is planned as part of this proposal. - The human proof-of-concept data in the application includes a computerized tomography scan (CT scan) and a ventilation/perfusion scan. One reviewer expected data from pulmonary function tests to be included in the application as convincing evidence that the airway could be patent during the full respiratory cycle. - Parameters for qualification and quality control for the decellularized scaffolds were insufficient in the proposal. References describe old techniques. - No description was provided for what would be planned for discussion at a key early regulatory meeting. Feasibility of the Project Plan - Reviewers were not convinced that the team could complete the IND enabling studies, the IND filing, and a Phase 1 study within the four-year timeframe. - Specifically, the panel questioned the feasibility of completing a Phase 1 study as planned in the proposal, given the aggressive enrollment plan and no allotment for a 12-month follow up period, which the panel felt to be standard regulatory practice at this time. - The panel felt the preclinical plan was generally adequate to be IND-enabling; however, success criteria were not clearly defined for key functional parameters. - The clinical plan was judged to have major flaws. Two examples provided were the use of subjective clinical descriptors for study entry and the proposed stopping rules. - The reviewers were divided on the need to study the proposed human product in preclinical models. Several reviewers felt that the studies could be accomplished with analogous constructs in the preclinical models, and that this could be discussed with the FDA prior to initiating key studies. Principal Investigator (PI) and Development Team - The PI was recognized as a leader in this cutting-edge technology, and his/her participation in the early case studies was acknowledged. - The preclinical team is comprised of strong partners who can deliver the non-clinical aspects of the project. - Participation by a pediatric surgeon with expertise in tracheal reconstruction who is credentialed at the home institution is critical to the project. At the time of the application, an individual had not yet been named. Collaborations, Resources and Environment - The applicant institution has excellent stem cell biology and tissue engineering capabilities, and possesses a unique asset to perform the preclinical studies. - The panel felt that the resources necessary to complete the proposed studies are in place in the applicant institution. Budget (Assessment of the budget was conducted separately from the overall scientific evaluation and points or concerns raised in this section did not contribute to the scientific score. This section highlights items that must be addressed should the application be approved for funding. ) - There appears to be a calculation error, since “the average cost per visit is $2.9M” which does not make sense. Other costs appear reasonable.