Hepatitis C and fatty liver disease are the two most common liver diseases in California. Individuals from different backgrounds are susceptible to these liver diseases, but they have unique genetic profiles that may influence the severity of disease and the response to specific therapies. Technology now makes it possible to generate stem cells from a person’s own skin. These cells can subsequently be used to generate liver cells identical to those from the original donor. Using this approach, scientists can perform research directly on an individual’s own liver cells to identify features that make the cells susceptible or resistant to disease and drug therapy. In this project, the research team will collect blood and skin tissue from people with liver disease and from healthy control subjects. The donated tissues will be placed in a "bank" for the production of stem cells. The overall goal is for the donated cells to be made available to scientists who will convert them to liver cells, and then carefully study them to learn more about liver disease. Research such as this is extremely valuable because it allows patients and volunteers to make a very personal contribution to the understanding of liver disease. The materials donated to this tissue "bank" will be a resource to the scientific community for many years.
Hepatitis C and fatty liver disease are the two most common liver diseases affecting the citizens of California. Together they afflict one in every 12 people in the state and kill roughly 4,000 state residents each year. Researchers in California are actively seeking new information about the causes of and treatments for liver disease; their progress will be greatly accelerated by the opportunity to directly study the biology of diseased patients. The goal of this project is to build a "bank" of stem cells from local patients with liver disease. Patient donors will come from many different backgrounds, reflecting the great diversity of California. The bank, once established, will be a tremendous resource for medical research because the banked cells will be renewable and made available to the entire research community. Banked stem cells will enable researchers to study the genetics and biology of liver disease and to test new therapies. Importantly, they will give researchers an opportunity to study liver disease in its most important context - the affected patient. The research made possible through this effort will greatly enhance our understanding of liver disease; this will in turn reduce the negative impact of liver disease on the health and well-being of California residents.
In this proposal, the applicant aims to collect skin biopsy/blood samples from healthy individuals and patients with hepatitis C or Non-alcoholic fatty liver diseases (Non alcoholic Steatohepatitis, NASH), two common liver diseases. The patients will be recruited to capture the diversity of these diseases across ethnic groups, treatment response and specific genotypes that impact response or susceptibility.
Impact and Significance
- The proposal targets two common liver diseases that are poorly understood at the cellular and molecular level. Reviewers agreed that cellular models of NASH in particular would be of tremendous benefit as tools for drug discovery and development.
- Characterization of patient clinical history coupled with genotypes associated with NASH and HCV prognosis will generate a unique tissue resource that should enable better understanding of molecular mechanisms of disease.
- Some reviewers noted that modeling of HCV infection in vitro using hiPSC could represent an opportunity to develop a new platform for drug screening, while others questioned the need given recent successes in HCV treatment of chronic HCV infection.
- Current animal and in vitro models for HCV are limited; therefore, modeling HCV infection in vitro using hIPSC derived hepatocytes could enable better understanding of individual patient infection and drug responses.
- A strong rationale is provided for the project and the two disease targets are compelling.
- The proposed patient sample size was reasonable, but reviewers thought the rationale for healthy controls especially in the context of HCV infection was weak given the difference was one of exposure to the virus that could be readily captured with other control cohorts
- Since the two diseases are known to primarily affect hepatocytes, the target lineage for differentiation for modeling is clear and logical.
- The methods for differentiation of iPSCs into hepatocytes are maturing and appear currently to be adequate for studying aspects of the HCV life cycle.
- Co-culture may be important for modeling HCV disease so the ability to derive other relevant cell types in addition to hepatocytes from iPSC lines should be considered more explicitly.
Quality of the Proposed Protocols
- The consent form is clear and consistent with the broad cell line utility and availability that are goals of the RFA.
- The proposal provided sufficient details how to manage and secure health information and coded in accordance with all relevant state and federal laws and regulations, although there was some question as to the adequacy of the database.
- The applicant has access to an established, relevant patient population and has an excellent track record of recruiting patients for participation in research.
- Reviewers were concerned about the risks of handling tissue from patients infected with HCV. Skin biopsies from these patients will require special care in handling, and appropriate containment. Additional screens for HCV and other viruses may be necessary. All these aspects could add challenges for hIPSC derivation.
- Proposed patient sample sizes seem reasonable particularly given results of recent genetic studies.
- While the applicant provides details reassuring that the number of patients proposed can be recruited, there is some concern about the logistics of collection of skin biopsies at multiple sites.
- In general reviewers thought the budget overall to be reasonable and to represent a good value for investment.
- While the budget is overall reasonable, it was not clear if all costs were included (e.g. costs for personnel to do the biopsy)..
- The applicant proposes to establish fibroblast cultures from biopsies which may be advantageous for practical purposes though the cost efficiency of this is unclear.
Qualifications of the Principal Investigator (PI) and Team Members, Resources
- The lead investigator has all the expertise, knowledge and experience necessary for this project to be successful.
- The track record of the team is impressive and will bring the appropriate clinical expertise to select and to recruit the right cohort of patients. The rationale and the feasibility of the proposal was strengthened by inclusion of a team member with knowledge of iPSC biology particularly as it relates to hepatocyte differentiation.
- PROGRAMMATIC DISCUSSION
- - A motion was made to move this application into Tier 1, Recommended for Funding. The panel felt the endoderm-derived lineage to be studied was of high merit, and noted that fatty liver was the only metabolic disease under consideration. The motion carried.
- - The application raised safety concerns regarding the potential presence of HCV in the samples that impacted the score. The panel agreed that the tissue collector must consult with the deriver to develop appropriate, separate handling procedures for this set of tissue samples to ensure safety.
- RECOMMENDED SHARED CONTROLS
- Reviewers argued that the numbers and characteristics of the proposed unaffected control tissue donors should be re-considered in the context of the entire spectrum of diseases recommended for inclusion in the CIRM hiPSC Initiative. Instead of each awardee collecting tissues from unaffected control individuals with only their disease cohort in mind, reviewers commented that in the context of the genetically complex diseases to be included in the CIRM hiPSC Initiative, it would be appropriate to include a well chosen group of tissue donors to serve as shared controls. Coordinating shared controls will also maximize effective use of funds for the CIRM hiPSC Initiative, as fewer total control tissue donors than proposed may be included.
- Reviewers recommended that a new cohort of unaffected control tissue donors be negotiated with the awardees, taking into consideration the age range, ethnicities and gender of all included diseased tissue donors. As this may affect the tissue donor number of individual applications, individual RFA 12-02 Award budgets will be adjusted accordingly during Pre-Funding Administrative Review.
- Jacob McCauley