How a Specialized DNA Technology Is Revolutionizing Rare Disease Treatment
Imagine visiting doctor after doctor, each one more baffled than the last, as you search for answers about a condition so rare that even specialists have never seen it before. For patients with rare genetic diseases, this frustrating scenario is an unfortunate reality. As one patient with lymphangioleiomyomatosis described her experience: "This woman is presenting this odd disease that no one knows how to treat, obviously no cure for, and she and her husband are sitting here looking at me all moon-eyed desperate for help with this dilemma they have been blind-sided with. What am I to do?... There simply are no set standards for this" 8 .
Known Rare Diseases
Approved Treatments
Are Genetic in Origin
This profound medical helplessness affects millions worldwide. With approximately 7,000 known rare diseases—most of them genetic in origin—and fewer than 500 approved treatments, the diagnostic odyssey can take years while patients and families navigate a daunting medical landscape often devoid of proven solutions 8 . But amidst these challenges, a revolution is quietly unfolding in biotechnology laboratories, where novel approaches to targeting the very building blocks of life are offering new hope.
At the heart of this story lies a sophisticated genetic technology called Locked Nucleic Acid (LNA). To understand its significance, we must first consider how our genetic machinery operates. Our bodies follow instructions encoded in DNA and RNA to produce proteins—the workhorses that carry out essential biological functions. When these genetic instructions contain errors, as happens in genetic disorders, the resulting proteins may malfunction, causing disease.
Think of RNA as a lock that needs to be opened or closed to control protein production, and LNA-based drugs as specially designed master keys that perfectly fit these locks.
LNA contains bridged molecules that "lock" the RNA into an ideal configuration for binding 1 .
"We believe the LNA drug platform offers a unique opportunity to develop drugs against the rapidly expanding number of disease targets in the rare genetic disorder space."
| Technology | Mechanism | Key Advantages | Limitations Overcome |
|---|---|---|---|
| LNA | Single-stranded oligonucleotides that bind to RNA | Very high binding affinity, doesn't require complex delivery vehicles | More stable than earlier antisense technologies |
| Early Antisense | Single-stranded DNA binding to RNA | Simple design | Low binding affinity, rapid degradation |
| siRNA | Double-stranded RNA that silences genes | High specificity | Requires complex delivery vehicles |
LNA-based drugs resist breakdown by the body's enzymes, remaining active longer than previous genetic therapies 9 .
They attach more securely to their target RNA, increasing potency many-fold over other nucleotide therapeutics 9 .
The technology allows drugs to potently and specifically inhibit RNA targets across many different tissues 1 .
The partnership between pharmaceutical company Shire and biotech firm Santaris represents a textbook example of how complementary expertise can accelerate medical innovation. Initiated in 2009 and extended in subsequent years, this strategic alliance brought together Santaris's cutting-edge LNA technology with Shire's extensive experience in developing and commercializing treatments for rare diseases 9 .
Original partnership agreement signed between Shire and Santaris
Santaris employs LNA platform against targets selected by Shire
Agreement extended to allow for more drug discovery programs
Translation of research into novel drugs for rare disease patients
"Our collaboration with Santaris is very important to us so we are very pleased with the decision to extend the agreement and allow for more drug discovery and development programs. Our hope is that the partnership will eventually translate into novel drugs that will help patients suffering from debilitating rare diseases lead better lives."
Early-stage payments for technology access and exclusivity
Upon successful completion of initial studies
Per drug candidate in development, regulatory, and sales milestones, plus royalties on commercialized products 9
| Aspect | Details |
|---|---|
| Initiation | Original deal signed in 2009 |
| Extension | Partnership later extended to allow more targets |
| Santaris's Role | Provide LNA Drug Platform for discovery |
| Shire's Role | Select targets, develop and commercialize drugs |
| Financial Terms | Upfront payments, research funding, milestones, and royalties |
To appreciate how LNA technology works in practice, let's examine a key experiment that demonstrates both the promise and challenges of this innovative approach. Researchers conducted a critical study to determine whether they could maintain an LNA-containing oligonucleotide library through multiple generations—a essential requirement for developing effective therapeutics 7 .
| Experimental Round | LNA-A Content | Change from Previous Round |
|---|---|---|
| Round 1 | 20.5% | Baseline |
| Round 4 | 9.9% | ~2-fold decrease |
| Round 7 | 6.6% | ~1.5-fold further decrease |
Similar experiments with LNA-T (thymidine) showed an even more dramatic reduction, with LNA-T content dropping 4.5-fold from 31.0% to just 6.8% after three rounds 7 . This clear preference for isolated LNA nucleotides over consecutive stretches provides crucial guidance for designing more effective LNA-based therapeutics.
This experiment revealed both the promise and limitations of LNA technology. On one hand, it demonstrated that LNA-modified libraries could be maintained for several rounds of selection—enough to potentially identify effective drug candidates. On the other hand, the gradual decline in LNA content highlighted the need for further refinement of the technology to improve stability during replication.
The research team concluded that "dispersed LNA monomers are tolerated in our in vitro selection protocol, and that LNA-modified libraries can be sustained for up to at least seven selection rounds, albeit at reduced levels" 7 . This capability enables the discovery of what scientists call "native LNA aptamers"—specially shaped LNA molecules that can bind to specific target molecules as potential therapeutics.
Developing LNA-based treatments requires specialized tools and reagents. Here's a look at the key components researchers use to create these innovative therapies:
| Research Tool | Function in LNA Research |
|---|---|
| LNA Oligonucleotides | Specially designed nucleic acids with locked structure for targeting specific RNA sequences |
| LNA Antisense GapmeRs | Used to silence specific genes by binding to messenger RNA and blocking protein production |
| LNA miRNA Inhibitors | Designed to block microRNA activity, potentially useful for cancer and other diseases |
| LNA-enhanced Detection Probes | Improve sensitivity in detecting RNA molecules for diagnostic purposes |
| KOD DNA Polymerase | Enzyme capable of incorporating LNA nucleotides into growing DNA strands |
| Phusion High Fidelity Polymerase | Used to amplify LNA-containing templates with high accuracy |
| Cycloheximide (CHX) | Chemical inhibitor that blocks nonsense-mediated decay, helping researchers study RNA with premature stop codons |
These tools have enabled researchers to overcome previous limitations in genetic medicine. As one study noted, LNA technology "overcomes the limitations of earlier antisense and siRNA technologies to deliver potent single-stranded LNA-based drug candidates across a multitude of disease states" 1 .
The extension of the Shire-Santaris partnership reflects a growing recognition that platform technologies like LNA represent the future of efficient drug development, particularly for rare diseases. The concept of platform technologies—defined as technologies that can be incorporated into multiple products and make development more efficient—is gaining traction among regulators and researchers alike 6 .
Traditional drug development models struggle due to small patient populations and the high costs of developing treatments for conditions that affect few people.
"Because the majority of rare diseases are genetic in nature, gene-editing modalities offer substantial promise" 2 .
The future of rare disease treatment may involve combining LNA technology with other innovative approaches, such as advanced RNA sequencing. Recent research has demonstrated that a "minimally invasive RNA-seq protocol using short-term cultured peripheral blood mononuclear cells (PBMCs)" can help detect splicing defects and other RNA abnormalities that cause disease . This is particularly relevant for neurodevelopmental disorders, where researchers found that up to 80% of genes associated with intellectual disability and epilepsy are expressed in PBMCs .
Of genes associated with intellectual disability and epilepsy are expressed in PBMCs
As regulatory agencies like the FDA and EMA work to create clearer pathways for platform technologies, the hope is that these innovations will significantly reduce the time and cost required to bring new treatments to patients. One analysis suggested that platform approaches could potentially decrease the time required to dose patients with a new gene-editing therapy "from years down to 6 months" 2 .
Platform technologies could reduce development time for new gene-editing therapies from years down to 6 months 2 .
The partnership between Shire and Santaris represents more than just a single collaboration—it exemplifies a shifting paradigm in how we approach some of medicine's most intractable challenges. By focusing on platform technologies that can be adapted to multiple conditions, rather than developing one-off treatments for each individual disease, researchers can create frameworks that dramatically accelerate therapeutic development.
For patients struggling with rare genetic disorders—who often face diagnostic odysseys, therapeutic dead ends, and feelings of isolation—these advances offer genuine hope. As one rare disease patient expressed, the desperate search for answers leads individuals and families to look to their doctors "all moon-eyed desperate for help with this dilemma they have been blind-sided with" 8 .
Through continued refinement of LNA technology, strategic partnerships between biotech innovators and pharmaceutical developers, and the evolution of regulatory frameworks that recognize the unique nature of platform technologies, we move closer to a future where rare no longer means untreated. Each scientific advance, each successful collaboration, and each new therapeutic candidate brings us closer to transforming the lives of patients who have waited too long for solutions.