Digestive Diseases Interagency Coordinating Committee
Novel Methods in Gene Therapy for Liver Disease
National Institutes of Health
- Encourage NIH grant support.
- Identify new target organs.
- Identify new target diseases.
- Develop accurate animal models.
- Support clinical trials.
- Optimize chimeric structures and delivery systems.
When asked by an attendee if chimeraplast efficiency could be increased through readministration, Dr. Steer stated that in the Gunn rat model for Crigler-Najjar syndrome, readministration caused the response to go from 25% reduction in bilirubin to 50% reduction. He mentioned that for many genetic abnormalities (e.g., Crigler-Najjar syndrome and hemophilia), 100% response is not required and that a 10-15% efficiency rate of hepatocyte transformation may be sufficient to see real improvement in clinical outcome. Another attendee asked whether there were any sequence requirements for candidate genomic targets. Dr. Steer replied that a GC-rich genomic region seems to work a bit better than an AT-rich region.
In response to a question on applications of chimeric oligonucleotides to bone marrow-targeted gene therapy, Dr. Steer commented that he is working with two University of Minnesota colleagues, Dr. R.P. Hebbel and Dr. C.M. Verfaillie, on gene correction of single point mutations in the beta globin gene in mouse models of sickle cell disease. He cited two challenges: identifying the hematopoietic stem cells and identifying receptors on stem cells that can be used to target and deliver the corrective chimeric oligonucleotides.
An attendee asked Dr. Steer to comment on possible applications of his technology to infectious diseases. Dr. Steer mentioned hepatitis B virus and hepatitis C virus infections as possible targets. An approach might involve the introduction of premature stop codons, but it would involve significant challenges and might require 100% gene conversion of extant viral genomes.
DDDN Liver Gene Therapy Portfolio
Jose Serrano, M.D., Ph.D., Director of Liver & Biliary and Pancreas Programs in the Division of Digestive Diseases and Nutrition of NIDDK, presented an overview of the Division's gene therapy portfolio. Overall, the researchers are interested in basic research in bile formation, liver growth and repair, and gene therapy. They also support basic and applied research in liver transplantation, preservation and storage of liver specimens, and clinical studies on hepatitis and genetic diseases.
Support mechanisms are 80% investigator-initiated R01 grants, with some R29 and R37. Other research areas include tumor biology, liver injury, cholestasis, bile acids, liver regeneration, and gallstones. The budget for gene and cell engineering has increased in the last few years from $1.6 million to $2.2 million and for the Liver & Biliary and Pancreas Programs overall has increased from $26 million in 1996 to $32 million in 1999.
Specific interests in gene and cell engineering include hepatocyte engineering, gene transfer methodologies, optimization of vectors, and mechanism of action studies.
Trans-NIDDK Gene Therapy Program
Catherine McKeon, Ph.D., Senior Advisor for Genetic Research in the Division of Diabetes, Endocrinology, and Metabolic Diseases of NIDDK, discussed the history and current status of extramural support from NIDDK for gene therapy. In the late 1980s, NIDDK decided to support basic development of gene therapy and issued a Request for Applications (RFA) in basic techniques of gene therapy for genetic diseases. Currently, NIDDK funds $13 million in extramural gene therapy research.
Unlike other parts of the NIDDK research portfolio, the gene therapy program is a little unusual in that it does not rely mainly on research grants. The program also uses pilot and feasibility grants, core centers, and small business innovation research (SBIR) grants. The SBIR grants are important because many small businesses are involved in gene therapy.
Initially, NIDDK used RFAs for gene therapy to generate a sufficient submission rate from investigators. Now, gene therapy is no longer so new and experimental. As a result, a sufficient number of proposals are being submitted, and the RFAs are not needed. Experimental and high-risk gene therapy protocols, however, are best funded through pilot and feasibility grants and have been funded since 1997. The current program announcement (PA) is PA-99-036 for R21 grants for $100,000 maximum for up to 2 years. Approximately 10 per year are being funded. The goal is to develop novel vectors and delivery systems targeted against inborn genetic diseases, for when a sustained, life-long therapeutic effect is required. Examples are long-term expression systems and repeat administration protocols.
Dr. McKeon next discussed the NIDDK gene therapy core center program, a P30 award in existence for about 5 years. These awards are for university-based facilities providing technological and resource assistance to gene therapy investigators campuswide. Examples include vector cores, animal cores, and histology cores. Four gene therapy core centers are currently funded by NIDDK.
NIDDK also participates with other NIH Institutes in supporting the National Gene Vector Laboratories, which manufacture clinical-grade gene therapy vectors, undertake toxicity studies, and support clinical trials in gene therapy. Dr. McKeon noted that they have initiated a master file on adeno-associated virus (AAV), which is currently in clinical trials for hemophilia and is being considered for several liver gene therapy projects. This AAV master file contains toxicological and manufacturing (cGMP) data on AAV vectors, and other clinical investigators can refer to this AAV master file when filing with the FDA, rather than repeating the AAV toxicology studies themselves.
NIDDK Strategic Plan
Ms. Carol Feld, Associate Director for Scientific Program and Policy Analysis at NIDDK, discussed the implementation process for the NIDDK Strategic Plan. The recommendation that NIDDK, along with all Institutes within the NIH, promulgate a Strategic Plan came out of a congressionally directed Institute of Medicine (IOM) study on improving NIH's setting of priorities and public input. Among the IOM recommendations that have been put in motion are that all NIH Institutes establish an Office of Public Liaison, that a Council of Public Representatives to the NIH Office of the Director be established, and that the Strategic Plans be formulated (they are due to be submitted in draft form to the NIH Director by December 31, 1999).
The NIDDK Strategic Plan will have the following features:
- Organization by cross-cutting scientific themes, rather than by diseases within the NIDDK research mission.
- A catalog of scientific opportunities and needs.
- Implementation strategies (what tools, reagents, techniques, and personnel are needed).
- Five-year time horizon.
- Public involvement.
- A final document written in lay language.
- A widely distributed plan, both electronically and in hard copy.
Requests for public input have been made to more than 70 voluntary and professional organizations with interests within NIDDK's disease mission, and a request for public input has also been posted on the NIDDK Web site. In addition, all of the Interagency Coordinating Committees (e.g., DDICC) have been enlisted to supply input into the NIDDK Strategic Plan.
The NIDDK Strategic Plan, which has also been the topic at several of the recent NIDDK Advisory Council meetings, will include sections on the following topics:
- Background--Magnitude of the burden of illness.
- Ongoing NIDDK planning processes.
- Highlights of the NIDDK research programs and accomplishments.
- Institute goals and objectives.
Five cross-cutting working groups have been established, each one chaired by a senior member of the NIDDK scientific staff:
- Genes and Disease--Regulation, Expression, Screening.
- Cells--Integration of Biological Mechanisms in Health.
- Causes and Mechanisms of Disease and Injury.
- Prevention and Treatment of Disease--Epidemiologic and Clinical Investigation.
- Infrastructure--Human Resources, Technology, and Research Facilities.
Ms. Rita Yeager, Senior Program Analyst in the Office of Scientific Program and Policy Analysis at NIDDK, presented an update on the status of the Department of Health and Human Services Appropriations Bill for fiscal year 2000 that is before the U.S. Congress. Ms. Yeager reported that this bill was still being marked up in the House and Senate subcommittees. House members were proposing an increase in the NIH budget of $1.35 billion; Senate members were proposing an increase of $2 billion for NIH; and the White House was proposing an increase of $0.32 billion.
Conclusion and Adjournment
Dr. Hoofnagle called on representatives of the Institutes present to provide an update on initiatives involving digestive diseases or gene therapy. He talked about a recent RFA that NIDDK had issued together with other Institutes and had contributed $3 million. Dr. Jorge Gomez of the NCI spoke about the NCI P50 center grants that have included digestive diseases, such as liver cancer and gastrointestinal cancers. Dr. Hoofnagle drew the attendees' attention to the 10th International Symposium on Viral Hepatitis and Liver Disease that is being sponsored by the Centers for Disease Control and Prevention and to an RFA on food safety and food-borne illness that NIDDK is drafting.
Dr. Hoofnagle noted that the next DDICC meeting is scheduled for December 14, 1999. The meeting adjourned at 10:30 a.m. on September 14, 1999.