Idiopathic Pulmonary Fibrosis (IPF) is a progressive and generally fatal disease that causes scarring of the lungs and therefore an inability to breathe. Its true prevalence is unknown, as it may go unrecognized for many years, but it is generally thought to affect more than 200,000 people in the USA and is five times more common than cystic fibrosis or amyotrophic lateral sclerosis. The mortality from the disease is very high with about two-thirds of patients dying within five years of diagnosis. The cause and reasons for progression of disease are unknown, but are likely complex and multifactorial, involving genetic predisposition and environmental exposures. A small percentage of cases run in families.
Our lack of therapies and understanding of IPF may in large part be due to the fact that there are no good models of the disease. Therefore, the potential development of a model of IPF from iPSC derived from IPF patients would be a major advance for the field and has the potential for drug and pathway discovery that would make a huge impact on patients’ lives. [REDACTED] has one of the largest IPF clinics on the west coast and has a Clinical Trials Group and a registry for IPF. Here we propose to recruit IPF patients from the IPF clinic to donate a blood sample for iPSC derivation. We will also track their demographic and medical data. These iPSCs will then be used for disease modeling of IPF followed by high throughput drug discovery testing to identify therapies for IPF.
Idiopathic pulmonary fibrosis (IPF) is a devastating fatal lung disease that usually occurs in the 7th decade of life. The disease causes scarring of the lungs that make it impossible to breath. The prevalence of IPF is on the rise and expected to double in the next 20 years as the U.S. population continues to age. The prevalence worldwide in the population that is greater than 65 years of age is predicted to be around 125 IPF cases per 100,000 people. California, the most populous state, is also the state with the largest number of people 65 years of age and over (3.6 million people in the year 2000) and therefore the prevalence of IPF in the USA is highest in California with over 5,000 cases.
By virtue of the severity of this disease, patients will almost always progress to end stage lung failure and the only therapy available is a lung transplant. In addition to the suffering and disability that IPF causes, the costs associated with caring for patients with IPF, including lung transplant costs, are extremely large. For example a single lung transplant costs roughly $400,000 and this doesn’t include all the follow up care needed post-transplant or any complications.
Improving our understanding of and identifying therapies for IPF will therefore have a major impact on patients in California with IPF. Firstly, it will reduce much pain and suffering and secondly it will reduce costs and free up donor lungs, that are in short supply, for other end stage lung disease patients.
The application describes the collection of blood samples for the generation of human induced pluripotent stem cells (hiPSC) from patients with Idiopathic Pulmonary Fibrosis (IPF) and from their friends or non-blood-related family members as controls. IPF is a poorly understood, and currently incurable, disease for which lung transplantation is the only definitive treatment. The team will collect a panel of demographic, clinical, and diagnostic data linked to each sample. The applicant outlines how in vitro models of IPF based on the directed differentiation of hiPSC into lung fibroblasts and lung epithelium may be used in future studies and in drug screening.
Impact and Significance
- IPF represents a substantial, unmet medical need. Since no good animal models of IPF exist, hiPSC-based models, if successful, could offer a novel approach to understanding the etiology of this disease and could have a significant impact on developing novel therapeutics and discovering biomarkers.
- Other than the few lines developed by the applicant, no IPF patient-specific hiPSC lines appear yet to exist; inclusion of the proposed patient population would thus contribute to a unique resource.
- The prevalence of IPF is relatively low, but at the minimum requested for this RFA.
- Reviewers were uncertain whether the targeted disease is easily amenable to hiPSC-based modeling. Since little is known about which lung cell lineages are involved in disease pathogenesis, it is not entirely clear which cell lineages should be derived for future disease modeling studies.
- Considering that derivation of mature lung epithelial cell lineages from hiPSC has not yet been achieved, reviewers expressed some concern whether the protocols for deriving such cell types will be developed in the near future, but also acknowledged that this limitation is likely to dissipate over the years as the required protocols are developed by the research community.
Quality of the Proposed Protocols
- The application contains a very comprehensive and well-written patient consent form.
- The medical and diagnostic information the applicant proposes to collect is excellent and reviewers praised the proposed longitudinal monitoring of IPF patient tissue donors.
- The management of tissue inventories and associated patient information is well thought out; the proposed data tracking system is proven, reliable, and secure within the applicant's facility. Adequate procedures are in place to ensure that protected health information is managed in compliance with applicable rules and regulations.
- Reviewers appreciated that some of the IPF patient tissue donors are predicted to be familial cases, albeit a small percentage, and thus suggested that a more focused effort be made to include more familial cases.
- The proposed activities are highly feasible. The applicant provides details assuring that software infrastructure and logistics are in place for sample procurement, tracking, shipping, and linking to protected clinical databases. Only one clinical site is involved with donor recruitment and tissue procurement, making the logistics straightforward.
- The applicant institution serves a rich IPF patient population and has an excellent track record of recruiting volunteers for participation in bio-repositories or trials. Reviewers were confident that the number of tissue donors proposed could be recruited based on the number of patients followed in the clinic and on historical participant numbers. Some concern may be warranted with regard to meeting the recruitment goals if the Deriver would require skin biopsies as opposed to blood collection.
- A letter from the Institutional Review Board suggests the proposal will be acceptable to them and the timeline to protocol approval will be rapid.
- The budget is overly large for the proposed work and the cost per donor blood sample procurement is very high. Especially the budget for personnel expenses is extremely high and the justification for the proposed number of personnel is not convincing. The responsibilities of various personnel appear to overlap significantly, and reviewers urged CIRM to negotiate lower personnel numbers and costs, if funded.
- Reviewers suggested that leveraging some of the data procurement already taking place at routine clinical intake might aid in personnel reduction.
Qualifications of the Principal Investigator (PI) and Team Members, Resources
- The PI is an experienced, well-funded clinician-researcher. The PI’s leadership is strength of this proposal.
- The team is experienced with donor recruitment, tissue collection and management of protected health information.
- The resources at the host institution are excellent with reliable access to the targeted patient population.
- Programmatic Discussion
- - A motion was made to move this application into Tier 1, “Recommended for Funding”. Reviewers considered this disease to be an important condition where a hiPSC resource would be a stimulus to the field. The motion passed.