Scientific Retreats 2010

Tuesday, March 23, 2010 (historical)

Session Topic: Oligonucleotide Therapeutics

Session Goals

This session will cover the current state of the science in oligonucleotide therapies, especially as it relates to diseases and conditions of interest to NIAMS. Current NIAMS-related oligonucleotide projects in the muscular dystrophies, and their possible outcomes and contributions to advancing other fields, will be covered. Finally, we will discuss scientific opportunities and needs for future, NIAMS-funded research.


Oligonucleotides are short nucleic acid polymers, typically with thirty or fewer bases, that are emerging as potential therapeutic agents for a wide range of diseases and disorders due to their ability to modulate molecular-genetic events, as well as protein-nucleic acid interactions. Oligonucleotide therapies have the potential to modify disease processes by addressing the genetic cause of the disease, as well as modify symptoms by targeting gene products downstream from the root cause. Oligonucleotides can be used to silence genes by promoting message degradation, to interfere with protein translation by preventing initiation, to alter the splicing pattern of an mRNA in order to skip a mutated exon, and to quench the ability of expanded repeats to sequester proteins. Oligonucleotide therapies may be useful in treating a wide range of diseases, including systemic lupus erythematosus, genodermatoses, infectious diseases, various forms of muscular dystrophy, and other neuromuscular diseases. Because oligonucleotides are sequence-specific, their development as pharmaceuticals presents unique challenges and will likely provide a basis on which other personalized medicine strategies can progress.

Current studies of oligonucleotide therapies focus on platforms for chemical synthesis, routes of delivery, efficiency of action, peptide conjugation for improved cell entry, and tissue targeting. Limitations include our lack of complete understanding of the mechanisms of action, concern about off-target effects, variability of effectiveness, potential toxicities, and expense of some chemistries. These may greatly complicate regulatory approval. Nonetheless, several clinical trials are underway to test oligonucleotide therapies for muscular dystrophies. Overcoming these obstacles may lead to a rapid advance in specific therapies and even personalized medicine for patients with arthritis, musculoskeletal, skin and other diseases.

Expected Outcomes

This session will identify research needs and opportunities in the area of oligonucleotide therapies. NIAMS staff will gain a better understanding of the role of the oligonucleotides in health and disease, especially as it relates to NIAMS interests. Staff will also gain knowledge of the many challenges currently faced by researchers in the field of oligonucleotide therapies.

Key Questions

  • What are the high priority basic research questions that are likely to lead to significant advances in oligonucleotide therapeutics?
  • How can the obstacles to large-scale synthesis (i.e., cost and yield) be overcome?
  • Since animal toxicity and efficacy studies may have limited usefulness in the testing of sequence-specific oligonucleotide therapeutics, what other types of studies could NIH support that provide data regarding pre-clinical efficacy and safety?
  • What roles might the NIAMS play in accelerating progress toward effective oligo therapies for diseases within its mission? What partnerships with patient advocacy organizations and academic and private sector researchers would help to advance this goal?