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RNAi for Gene Transfer Approaches to Heart, Lung, and Blood Diseases

Executive Summary

I. Introduction

Experts in the biology of RNA interference and the application of RNA interference in in vivo settings met on July 19, 2004 in Bethesda, Maryland to identify opportunities and challenges for incorporating the tools of RNA interference into existing gene therapy approaches for heart, lung, and blood diseases, based upon the current state of the science.

An overview of the RNAi mechanism led to significant discussion of specificity of the process and whether RNAi could ever be harnessed as a mono-specific targeting mechanism for suppressing gene activity. Concerns were raised about off-target effects (1) at the level of mRNA degradation, and (2), perhaps more prominently, at the level of interference with protein synthesis. It was generally agreed that additional research stimulation via NHLBI initiatives is probably not necessary for the former but would be desirable for the latter, particularly since tools for addressing this issue are scant.

Efforts to use RNAi as a way to screen for new targets for conventional drug development, rather than as a therapeutic tool, were discussed. The Working Group debated whether this approach could be expanded beyond gene therapy to include target discovery, since target discovery and validation are likely to be where RNAi would have its first major impact on treating disease.

Delivery of siRNA and shRNA to the liver, by using hydrodynamic methods and AAV as gene delivery vehicles, were considered. Recent research using different AAV serotypes has shown vast differences in the efficiency of delivery, depending upon origin of the virus coat protein, and very good suppression of target proteins. Although some problems with long-term toxicity were observed, these seemed surmountable.

An alternative approach toward using shRNAs in gene therapy--the use of lentiviral vectors to deliver shRNA expression cassettes—was explored. Several groups of researchers have demonstrated delivery of shRNAs to stem cell progenitors in hematopoietic systems; this is directly relevant to the NHLBI’s mission. Use of RNAi to combat HIV infection and the design of a possible clinical trial were presented, which provoked a great deal of discussion regarding the best way to test the potential of RNAi in the clinic and whether RNAi would be subject to the same types of scrutiny, by the Food and Drug Administration, as are antisense preparations and gene therapy per se.

Finally, research on using siRNAs themselves as therapeutic agents was presented. A novel agent has shown promise in mediating delivery of siRNAs in vivo; however, the focus of this work was delivery to the liver.

II. Recommendations

The Working Group then went on to discuss specific recommendations for targeted research opportunities that fall within the NHLBI’s purview. Although the general consensus was that most of the progress in models had been made in the hematopoietic system, the NHLBI should consider placing some emphasis on delivery of these agents via inhalation. The next logical step would be for the NHLBI to organize a conference that would bring together experts from the disciplines of disease biology, gene therapy, and RNAi research to identify specific therapeutic opportunities relevant to the NHLBI mission. This would be followed by a targeted initiative to fund research on RNAi in diseases of the heart, lung, and blood.

The specific recommendations are that the NHLBI should:

  • Organize a meeting of invited speakers to focus exclusively on diseases relevant to the mission of the NHLBI. These participants should be joined by invited speakers who are intimately involved in developing approaches for gene delivery and for delivery of nucleic acids in a systemic or targeted fashion, as well as by experts on RNAi.
  • Discuss, with the invited participants, the formation and funding of consortia to take focused and innovative approaches to the application of RNAi to treat heart, lung, and blood diseases.
  • Follow the meeting with an initiative to fund consortia that would focus on specific issues. Issues might include:
    • Using this technology for therapeutics in the delivery and uptake process of RNAi in various tissues, which is not clearly understood at present.
    • Exploring the stability and half-life of RNAi, and its potential toxicity in treating diseases such as heart, lung, and blood diseases.
  • Consider funding research centers to apply existing RNAi-based tools, such as libraries of siRNAs and shRNAs, to identify new therapeutic targets for conventional drug discovery.
  • Encourage the use of non-human primate models to facilitate translation of basic science to clinical applications in RNAi therapy.

Working Group Members


  • Gregory Hannon, Ph.D., Professor, Cold Spring Harbor Laboratory


  • Beverly L. Davidson, Ph.D., Roy J. and Lucille J. Carver College of Medicine, University of Iowa
  • Natasha Caplen, Ph.D., Office of the Director, Center for Cancer Research, National Cancer Institute, NIH
  • Mark A. Kay, M.D., Ph.D., Professor, Director, Program in Human Gene Therapy, Stanford University School of Medicine
  • John J. Rossi, Ph.D., Chairman, Division of Molecular Biology, Beckman Research Institute of the City of Hope
  • Philip A. Sharp, Ph.D., Institute Professor and Director of the McGovern Institute, Massachusetts Institute of Technology
  • Erwei Song, M.D.,Ph.D., CBR Institute of Biomedical Research, Harvard Medical School

NHLBI Staff:

  • Sonia I. Skarlatos, Ph.D., National Heart, Lung, and Blood Institute
  • Pothur Srinivas, Ph.D., National Heart, Lung, and Blood Institute

Last updated: September 23, 2004

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