A look back at the revolutionary IBC Sixth International Conference that marked a turning point in genetic medicine
In the spring of 1999, something remarkable was happening in the world of medicine. At the IBC Sixth International Conference on Oligonucleotide Therapeutics in La Jolla, California, scientists were discussing a revolutionary approach to treating disease—one that wouldn't just interfere with proteins in the body, but would go straight to the genetic source of the problem itself.
Just months earlier, the first oligonucleotide drug, Vitravene, had received FDA approval for treating a sight-threatening viral infection in AIDS patients 3 8 . This milestone marked the culmination of two decades of research and offered a glimpse into a future where countless genetic disorders might be treatable.
The excitement at that 1999 conference was palpable—researchers were standing at the threshold of a new era in medicine, armed with molecules that could, in theory, target any gene of interest with exquisite precision 8 .
The 1999 conference came at a pivotal moment - just after the first oligonucleotide therapeutic received FDA approval.
So what exactly are oligonucleotide therapeutics? The concept is elegantly simple. Imagine your genes as recipes in a cookbook, and messenger RNA (mRNA) as photocopies of those recipes that get sent to the kitchen to make dishes (proteins). Sometimes, harmful recipes get copied—like those from a virus or a mutated gene—leading to "dishes" that cause disease.
Oligonucleotide therapeutics work by sending in a custom-designed antisense molecule—a short string of genetic letters (about 15-20 nucleotides long) that is the mirror image of a section of the problematic recipe 3 8 .
When this antisense molecule finds its target, it locks onto it, effectively placing a piece of tape over that part of the recipe so the kitchen staff can't read it. This either blocks the harmful protein from being made or marks the mRNA for destruction 3 .
The beauty of this approach is its potential specificity. Traditional drugs often interact with multiple proteins in the body, causing side effects. In principle, antisense oligonucleotides could be designed to target only one specific problematic gene, offering the promise of highly targeted treatments with fewer side effects 8 .
In 1999, researchers had several chemical variations of oligonucleotides in their toolkit. Creating effective therapeutic oligonucleotides wasn't as simple as just stringing together the right genetic letters—the natural molecules would be quickly destroyed in the body. The key breakthroughs came from chemically modifying the oligonucleotides to make them more stable and effective.
| Research Reagent | Function/Benefit |
|---|---|
| Phosphorothioate Bonds | First-generation modification; replaces oxygen with sulfur in the oligonucleotide backbone to increase stability against degradation in the bloodstream 3 8 . |
| 2'-O-Methyl & 2'-MOE | Second-generation sugar modifications; increase binding affinity to target RNA and further improve stability, reducing the frequency of dosing required 3 8 . |
| Peptide Nucleic Acids (PNA) | Synthetic DNA/RNA analogs where the sugar-phosphate backbone is replaced by a peptide-like structure; exceptionally high binding affinity and resistance to degradation 3 . |
| Morpholino Oligomers | Another synthetic analog using a different backbone structure; known for excellent sequence specificity and minimal non-antisense effects 3 . |
| Lipid Nanoparticles | Early delivery systems that package oligonucleotides in fatty particles to help them cross cellular membranes and reach their intracellular targets 1 . |
The most exciting discussions at the 1999 conference likely centered on "gapmer" designs—sophisticated oligonucleotides that combined different modifications. These typically had a central block of DNA-like nucleotides (to recruit the destructive RNase H enzyme) flanked by modified ends that protected the molecule from degradation 3 8 . This design represented the cutting edge of therapeutic oligonucleotide engineering in 1999.
Combination of different modifications in a single molecule for optimal performance.
While the La Jolla conference featured numerous presentations, one representative type of experiment from that era illustrates how researchers were testing these new therapeutic molecules. The following describes a typical in vitro experiment that would have been presented at such a conference, demonstrating the potential of antisense technology.
Researchers designed a 18-mer antisense oligonucleotide complementary to the translation start site (including the AUG codon) of the target mRNA. A control sequence with the same nucleotide composition but scrambled order was also created 9 .
The antisense and control oligonucleotides were synthesized with phosphorothioate modifications throughout their backbone to enhance stability against cellular nucleases 3 8 .
Human cell lines expressing the target gene were grown in standard conditions. The oligonucleotides were introduced into the cells using lipid-based transfection reagents, which help the negatively charged molecules cross the cell membrane .
After 24-48 hours of exposure, cells were harvested. Protein levels were measured by Western blot, and mRNA levels were assessed by Northern blot analysis .
The experiment provided clear evidence supporting the antisense mechanism of action:
The data showed that the antisense oligonucleotide specifically reduced the target protein to barely detectable levels, while the control sequences had no effect. Cell viability remained high across all conditions, suggesting the effect wasn't due to general toxicity .
The parallel reduction of both mRNA and protein indicated that the phosphorothioate-modified antisense oligonucleotide was working primarily through the RNase H mechanism—where the binding of the DNA-like oligonucleotide to its mRNA target triggers the enzymatic destruction of that mRNA 3 8 .
Targeting the AUG start codon region typically produced the most potent inhibition, a valuable insight for designing effective therapeutic oligonucleotides 9 .
By May 1999, the clinical potential of oligonucleotide therapeutics was already being explored across a surprising range of diseases. The first approved drug, Vitravene (fomivirsen), developed by Ionis Pharmaceuticals and Novartis, gave the field tremendous validation 8 .
Most of these early clinical candidates were first-generation molecules with phosphorothioate modifications, administered either locally (like Vitravene's injection into the eye) or systemically 8 .
The field was already looking ahead to second-generation chemistries that would be more potent, longer-lasting, and better tolerated. Researchers were exploring ways to improve delivery to target tissues and reduce potential side effects.
The mood at the 1999 La Jolla conference was one of cautious optimism. As one review from that year noted, "Similar to other novel medicines, the path to success has been lined with numerous failures" 3 . Scientists recognized the significant hurdles that remained—especially improving delivery to target tissues and reducing potential side effects.
Yet, the atmosphere was electric with possibility. Researchers had proven that synthetic oligonucleotides could be designed to selectively interrupt disease processes at their genetic roots. The first drug was on the market, and the science was advancing rapidly. They were building a comprehensive toolkit—with increasingly sophisticated chemical modifications, delivery systems, and design principles—that would enable this new class of medicines to mature.
Looking back from 2025, where the oligonucleotide therapeutics market is projected to reach $9-11 billion 1 , the significance of that 1999 conference is clear. The researchers gathering in La Jolla were participating in a pivotal moment—they were witnessing the transition of oligonucleotide therapeutics from an intriguing laboratory concept to a validated, powerful new platform for medicine that would eventually help thousands of patients with previously untreatable genetic conditions.
This conference marked a turning point where oligonucleotide therapeutics transitioned from theory to clinical reality.