Disease Team Research I
The primary goal of our Airway Team 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 a first-in-human surgical success with a stem cell-based tissue engineered airway implant in a compassionate care case in a young adult. To this end, we will perform the necessary preclinical studies to support a successful FDA application within 4 years. We propose to use stem/progenitor cells from the patient to treat an extraordinarily difficult-to-manage health problem in children, namely tracheobronchomalacia (TBM). TBM in children is a disease that leads to collapse of tracheal cartilage causing severe airway obstruction that is life-threatening. It occurs in approximately 200 California children each year and the morbidity and mortality associated with this disease is very high. Approximately 25% of these young patients die before their first birthday. 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 in these children and a normal quality of life. Our Airway 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, a stem cell-based, tissue engineered tracheal implant was successfully used by our Airway Team partners to save a young woman’s life. This first-in-human study emphasizes that our goal is realistic and paves the way for Phase I/II trials in children. Stem/progenitor cell-derived airway transplants that use the patient's cells have the clinical advantage of not requiring anti-rejection medications long-term. 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 this proof-of-principle, compassionate care case, there is substantial work that must be done before considering such transplants for pediatric patients, and on a large scale, for adults. We address this challenge with our Airway Team and emphasize the synergism resulting from linking Team members with expertise in a variety of related 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 in the State of California that 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. The Airway Team proposes to use stem cells to cure an extraordinarily difficult-to-manage and life-threatening health problem in children. Tracheobronchomalacia (TBM) in children is a disease that leads to severe airway obstruction and occurs in approximately 200 California children each year. The morbidity and mortality associated with this disease is very high; approximately 25% of patients will die before their first birthday. TBM in children is our target disease, but the knowledge gained from the preclinical studies proposed will provide a new technology that can be applied to other disorders in California populations. We foresee that our stem cell-derived airway transplant could be applied to treat adults with severe tracheomalacia associated with lifelong bronchitis and 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 potentially even patients with debilitating laryngeal scarring. Given that the prevalence rate of COPD for California citizens >65 years of age approaches 8-10%, if even 0.1% of COPD patients in California were candidates, then >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. An additional benefit for California citizens will be the establishment of a scientific and clinical Center of Excellence in Airway Disorders in California. The Airway Team project will provide a cornerstone of a larger Airway Center that will serve a diverse population of California patients. Our Team will provide the impetus to better coordinate and share the considerable knowledge and resources that are presently used to treat adults and children with COPD, asthma, cystic fibrosis, and other upper airway disorders for which new treatment options are desperately needed.
The goal of this four-year project is to develop an autologous tissue-engineered airway for tracheobronchialmalacia (TBM), a life threatening disorder, which in children has a 25% mortality by year 1 and lifelong morbidity thereafter. The proposed therapeutic candidate utilizes a decellularized tracheal scaffold repopulated with a combination of autologous chondrocytes derived from mesenchymal stem cells (MSC) and airway epithelial cells. This approach is based upon the application of this method to an adult patient, on compassionate grounds, in the Partner PI's country. In order to translate this technology to a pediatric population, the applicant plans to optimize and automate cell/scaffold production, conduct a bioethics evaluation, conduct long-term preclinical durability and safety studies, and prepare and file an Investigational New Drug application (IND) with the FDA. Overall, while reviewers appreciated the scientific rationale and potential impact of this proposal, they raised a number of concerns about the feasibility of the plan and the team’s ability to execute aspects of the proposed work. Specifically, reviewers judged that the applicant team had not adequately addressed a major technical hurdle in the plan, nor incorporated pediatric expertise; both are required to successfully translate the proposed therapeutic approach to a pediatric population. Reviewers agreed that scientific rationale for this proposal is strong, based on the pioneering approach that has been used in first-in-human studies in two adult patients in the Partner PI's country. Reviewers appreciated the need for alternative tracheal reconstruction strategies in the subpopulation of patients for whom conventional treatment fails or is not indicated, and agreed that if successful, this approach could potentially address the most challenging cases. While the potential patient population is not expansive, one reviewer commented that the advances made by this research team could serve as a platform for other tissue engineering applications. Because of the strong preliminary data, this project was judged to be of sufficient scientific maturity to result in an IND filing within four years, given an appropriate preclinical research plan and appropriate expertise. Reviewers noted that significant preclinical work has already been completed in a clinically relevant model and in two first-in-human cases. Preliminary preclinical results indicate proof-of-concept for immune tolerance, short-term function, and appropriate histology. The panel felt that, in general, these data support moving forward with such an approach, but it was not clear from the proposal how the results from two adult patients would translate to pediatric patients. All reviewers noted significant issues with the research plan that called into question the project’s feasibility as proposed. A major concern from the first-in-human studies was raised, which called into question the durability of such grafts. Reviewers judged that the applicant team had not adequately addressed development of a neovascular circulatory interface between the host and graft. One reviewer noted that the proposed solution to address blood supply to the transplanted segment had been attempted in the past and had been shown to fail in multiple publications. Additionally, preclinical outcomes would need to be extended well beyond the 30 days proposed in the preclinical model studies to be more consistent with the timeline in which re-stenosis, a possible consequence of post-transplant ischemia, has developed in one patient. Reviewers noted that the applicant team had not adequately addressed a plan to assess the cellular and humoral response to foreign antigen in vivo and alternatives were not presented if an immune response occurred. The engineered-segment’s response to growth of the host may be an issue in infants and should be addressed in the preclinical plan. The preclinical and development plan was judged to be relatively complete from a regulatory perspective, with necessary activities outlined and appropriate preclinical safety and regulatory go/no go decisions. All reviewers noted the novel inclusion of a bioethics evaluation, but one reviewer commented that it needed to be more fully developed in order to be useful in future clinical studies. Reviewers found the inexperience of the research team in the treatment of this condition in pediatric patients to be a major concern. The research team was comprised of California scientists in collaboration with a group funded by a CIRM Collaborative Funding Partner (CFP). Reviewers found little evidence of publication or training in congenital diseases or malformations of the airway, stem cells, or bioengineering for the California-based PI, at least one of which would be critical to lead a project of this magnitude. The Co-PIs bring strengths in preclinical models and imaging. One Co-PI was judged to be an experienced investigator with considerable experience in stem cell research and clinically-relevant models in a wide variety of preclinical settings. Another Co-PI with training in otolaryngology was judged to be well-suited to oversee the surgical procedures and techniques to assess the tracheal implants. The absence of a pediatric surgeon experienced in tracheal reconstruction was a judged to be a major gap. The Partner PI’s contribution to the pioneering study and his/her long-term commitment to the field of airway reconstruction and transplantation were praised by all reviewers. The Partner PI’s participation was judged to be critical to the project, and the review panel recognized the “turn-key” capability that the CFP team brings to the project. However, the review panel did not have confidence that the California-based team as structured in the application could achieve the goals of the research proposal. Reviewers agreed that the resources and facilities are more than adequate to complete the proposed project. They noted that the key collaboration brings together many essential ingredients including stem cell expertise, cGMP manufacturing, and preclinical modeling with tissue engineering. Overall, while reviewers agreed that this proposal addresses an important unmet medical need and could potentially have a significant impact, they were not convinced of the research team’s ability to execute the research plan without further consideration of problems that might appear along the developmental timeline. As a result, the reviewers did not believe the proposal would result in an IND filing within the 4-year timeframe.
- Andrew Balber