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

Bethesda, Md



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.



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