The sometimes twisty, sometimes intuitive, sometimes amazingly elegant hidden logic of the natural world has always fascinated Dr. Timothy Yu. Knowledge we now take for granted — the genetic code, machinery of transcription, or the layered biological logic of developmental patterning — were once completely mysterious. The ability to discover this hidden knowledge and apply it in the real world to help patients has inspired Dr. Yu throughout his career.

Following his north star: education and training

While Tim is now a neurogeneticist at Boston Children’s Hospital and Harvard Medical School, he grew up in San Diego, where his parents pursued careers in medical research. As a kid, he was unaware of much of their work, but when he went to his mother’s clinic at UCSD Medical Center as a teenager, he was struck by what he saw: young children with Leukemia in hospital gowns, attached to IV poles, bald from their chemotherapy. His mother, a typically cheerful pediatric hematologist and oncologist, told him that half of the kids he’d seen wouldn’t make it.

Shocked, he asked, “Isn’t that so depressing? Why in the world do you do this? Her response: “Actually, when I started 20 years ago, we lost 90% of them. So from my perspective, I’m really proud we’re able to save half.”

Tim followed in his parents’ science-shaped footsteps, studying biochemistry and molecular biology at Harvard College, and then neuroscience in graduate school at the University of California, San Francisco. Approaching the completion of his MD-PhD program, he had to decide: spend years in more medical training, or fast-track into basic science?

After a great deal of soul searching, he decided he wanted to pursue work anchored in real-world problems. Rather than choosing science for science’s sake — getting grants, giving talks, publishing important papers — he believed the truest demonstration of understanding a subject was to show you could put your knowledge to good use.

“This felt to me like a north star: seeing an idea implemented in the real world, for some useful practical purpose. For me, it translated to reaffirming my commitment to the physician-scientist route.”

That decision made, he had to choose a specialty for residency. He noticed many of his peers chose their fields based on their personalities.

“A sort of ‘Sorting Hat’ quiz — based on your personality type, and whether it matched the stereotype of what a particular medical subspecialist was supposed to be like? Friendly, good with kids? Pediatrics or family medicine for you. Like dimly lit rooms, microscopes? Radiologist or pathologist. Like to cut? Surgery for you.”

As he reflected on what to choose, he thought of his mother’s words 15 years ago, on that visit to his mother’s clinic. He decided not to choose a field based on how it looked presently, but on where it was headed, what problems needed to be solved, and where he could see the field going over the next 20 years and where, if given the opportunity, he could help take it.

Encountering antisense technology: finicky and satisfyingly mysterious

Tim did his neurology residency at Massachusetts General Hospital and Brigham and Women’s Hospital, followed by a fellowship in neurodevelopmental genetics at Massachusetts General Hospital and Boston Children’s Hospital. He began groundbreaking work in diagnostic personalized medicine, becoming one of the first to use genome-scale sequencing to identify a human disease gene in 2010 (1). In 2013, he published a key study applying exome sequencing to uncover rare genetic causes of Autism spectrum disorder, which highlighted recessive contributions (2). His research group continues to use advanced sequencing and analytics to understand the genetics of autism and other brain development disorders. These tools have also been translated to the hospital, where analyses of rapid-turnaround genomic sequencing are conducted in both the neonatal intensive care unit and the newborn nursery. However, it would be his later work with antisense technology that would change not only his research but also the field of rare diseases.

Before earning his medical degree, Tim first heard of antisense during his undergraduate years at Harvard in the early 1990s, when one of his classmates in the lab next to his was using antisense oligonucleotides to block gene expression in mammalian cell culture.

“As I remember it, the technology was simple in concept, but it seemed annoyingly finicky and mysterious,” he says.

The next time he encountered antisense technology was in graduate school a few years later, and this time he used it to identify his first disease-causing gene in a worm brain. Surfing the C. elegans genome, he had discovered a worm ortholog of an interesting neuronal cytoskeletal protein on chromosome 5, suspiciously close to unc-34, a mapped genetic locus that, when mutated, caused severe miswiring defects in the worm brain. Knocking down this gene by injecting an antisense oligonucleotide phenocopied the unc-34 phenotype, proving that it was the causative gene. But it was his encounter with the technology in 2017 that proved to be the most important, and which would reshape the direction of his research.

Building a framework for the ‘long tail’ of genetic disease

In January 2017, he came across a Facebook post connecting him to a Colorado family whose daughter had a terrible neurodegenerative disease. Their daughter, Mila, had just been diagnosed with Batten disease, a rare and cruelly progressive condition that impacts around 100 children born in the United States every year. Using their expertise in genome sequencing, Tim and his research group identified a tricky mutation that had eluded detection in Mila’s previous clinical workup; this allowed them to confirm her diagnosis and determine that her brother was not at risk for the disease.

“But we also realized that her unusual mutation could, at least in principle, be correctable with an antisense oligonucleotide,” Tim explains. “The only problem was, who could possibly develop such a drug? Her mutation was at that point — and to this day remains — unique to her — an “N=1.”

The team began speaking to everyone they could think of for advice and, in the end, decided they would have to make the therapy themselves. This would be the world’s first individualized ASO drug tailored to a single patient (3), and while Mila eventually passed away from her condition, her bespoke therapy suppressed her seizures and improved her quality of life. Tim says it was also the start of a remarkable odyssey that, over the past eight years, drew him into the OTS community, reshaped the direction of his research group, and been the source and inspiration of some of the most prized personal and professional partnerships with oligo, rare disease, CMC, and regulatory experts across academia, government, the private sector, and beyond.

“Over and over again, I’ve been struck by the generosity of our OTS community, and their willingness to help their fellow colleagues, and maximize the therapeutic potential of this field,” he says.

Tim lists the therapy they created for Mila, called milasen, as a proud achievement. Since then, he and his team have created several other personalized medicines, including atipeksen (4), for a young girl with a genetic disorder called A-T, or ataxia-telangiectasia, which causes severe neurodegeneration and shortens a person’s life span by an average of 25 years, as well as valeriasen, for a young girl named Valeria with a rare and devastating form of epilepsy (5).

“I’m also proud that two of our programs — one for A-T and one for Niemann Pick type C — led to the first patients to be treated with individualized ASOs in Europe and the UK, respectively, in collaboration with Matthis Synofzik of the University of Tubingen, and Haiyan Zhou and Paul Gissen of University College London and GOSH, respectively,” he says.

These therapies, together with programs led by Neil Shneider and Ionis, and Bob Brown and Jon Watts, set the tone for a productive Critical Path Innovation Meeting with the FDA in 2019, Tim says, which led to the release of the first regulatory draft guidelines for the development of individualized drugs in 2021.

“These have in turn cracked open the door for many, many others to apply genetically precise therapeutic technologies to orphan diseases,” he says.

Beyond the lab, Tim is immensely proud of the N=1 Collaborative, which he founded with Mila’s mother, Julia Vitarello, to advance the international effort to develop individualized therapies for rare diseases. Tim says that what started as a small OTS task force (led by Art Krieg, Annemieke Aartsma-Rus, Jon Watts, and Keith Gagnon) has now grown into a vibrant community working together to make individualized therapeutic approaches safe, affordable, and accessible.

“It’s been a privilege to work alongside such generous contributors to build a framework for the ‘long tail’ of genetic disease,” he says.

Future directions of OTS research and advice for young scientists

The creation of the N=1 therapies is a significant development in the field, and last year, the story of baby KJ and the creation of a bespoke therapy for his rare condition brought public awareness of individualized medicine up another notch, says Tim. Additionally, at the end of 2025, the FDA’s announcement of the plausible mechanism pathway (6), as well as a similar announcement by the MHRA (7), reflects a shift in regulatory readiness for individualized medicine, which Tim says is an acknowledgment that “the time is now.”

As new and more effective chemistries and delivery methods roll out, Tim says each has the potential to improve the therapeutic index and unlock the true programmable potential of oligonucleotide drugs. Additionally, Tim says AI can be an essential strategic enabler that helps guide us more efficiently towards the critical physiochemical, molecular biological, and cellular parameters required to develop safe and successful drugs.

“It will never replace experiments entirely, but will likely help us navigate sequence space more efficiently.”

As for young scientists entering the field, Tim’s advice is to work hard, talk to everyone, and cross-train wherever you can because “the most significant advances in science are usually made at the intersection of disciplines.” Additionally, he encourages scientists to embrace ideas that may feel “big, risky, and unlikely to work,” because it is their job as scientists to tackle important problems.

“We try to think problems through from first principles, to explore what’s scientifically, clinically, and ethically possible — and make it happen. But sometimes that takes us into unfamiliar territory. People pause and ask: Wait—can we really do that?” he says. “It’s natural for people to be uncomfortable. You have to think through all of the angles, be careful. Pressure test your ideas with experts. Be willing to be challenged. Then, if you’re convinced, you have to walk others through it to convince them. You have to talk to a lot of people, in their languages.”

Personal life and legacy: no disease is too rare for attention

The work is demanding, but Tim is grateful for his dedicated team, some of whom have been with him for a decade. He also finds equilibrium through his family.

“Having three kids aged 11 through 15 who are smart and sassy is a very effective way of staying grounded,” he says. Cooking, playing the piano, and, when he has the chance, hiking with the kids and using his long lens to photograph birds and wildlife are among his favorite activities outside the lab. “And sports are a fantastic centering activity for me: tennis, badminton, squash, pickleball.”

Asked what one thing he would want to be remembered for, Tim says it would be forging a path for a new field of “interventional genetics”— marrying science, drug development, and responsible medicine — for the benefit of patients, no matter how “rare” their disease. “The oligonucleotide technology that has been developed by the OTS community has an incredibly broad reach — working together, let’s maximize it.”

To stay up to date with Dr. Tim Yu’s latest research and contributions, visit his lab website here and watch the N1C seminars here.

To read the mentioned research articles, see the list below:

1. Yu TW, Mochida GH, Tischfield DJ, Sgaier SK, Flores-Sarnat L, Sergi CM, Topçu M, McDonald MT, Barry BJ, Felie JM, Sunu C, Dobyns WB, Folkerth RD, Barkovich AJ, Walsh CA. Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nat Genet. 2010 Nov;42(11):1015-20. doi: 10.1038/ng.683. Epub 2010 Oct 3. PMID: 20890278; PMCID: PMC2969850.
2. Yu TW, Chahrour MH, Coulter ME, Jiralerspong S, Okamura-Ikeda K, Ataman B, Schmitz-Abe K, Harmin DA, Adli M, Malik AN, D’Gama AM, Lim ET, Sanders SJ, Mochida GH, Partlow JN, Sunu CM, Felie JM, Rodriguez J, Nasir RH, Ware J, Joseph RM, Hill RS, Kwan BY, Al-Saffar M, Mukaddes NM, Hashmi A, Balkhy S, Gascon GG, Hisama FM, LeClair E, Poduri A, Oner O, Al-Saad S, Al-Awadi SA, Bastaki L, Ben-Omran T, Teebi AS, Al-Gazali L, Eapen V, Stevens CR, Rappaport L, Gabriel SB, Markianos K, State MW, Greenberg ME, Taniguchi H, Braverman NE, Morrow EM, Walsh CA. Using whole-exome sequencing to identify inherited causes of autism. Neuron. 2013 Jan 23;77(2):259-73. doi: 10.1016/j.neuron.2012.11.002. PMID: 23352163; PMCID: PMC3694430.
3. Kim J, Hu C, Moufawad El Achkar C, Black LE, Douville J, Larson A, Pendergast MK, Goldkind SF, Lee EA, Kuniholm A, Soucy A, Vaze J, Belur NR, Fredriksen K, Stojkovska I, Tsytsykova A, Armant M, DiDonato RL, Choi J, Cornelissen L, Pereira LM, Augustine EF, Genetti CA, Dies K, Barton B, Williams L, Goodlett BD, Riley BL, Pasternak A, Berry ER, Pflock KA, Chu S, Reed C, Tyndall K, Agrawal PB, Beggs AH, Grant PE, Urion DK, Snyder RO, Waisbren SE, Poduri A, Park PJ, Patterson A, Biffi A, Mazzulli JR, Bodamer O, Berde CB, Yu TW. Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease. N Engl J Med. 2019 Oct 24;381(17):1644-1652. doi: 10.1056/NEJMoa1813279. Epub 2019 Oct 9. PMID: 31597037; PMCID: PMC6961983.
4. Kim J, Woo S, de Gusmao CM, Zhao B, Chin DH, DiDonato RL, Nguyen MA, Nakayama T, Hu CA, Soucy A, Kuniholm A, Thornton JK, Riccardi O, Friedman DA, El Achkar CM, Dash Z, Cornelissen L, Donado C, Faour KNW, Bush LW, Suslovitch V, Lentucci C, Park PJ, Lee EA, Patterson A, Philippakis AA, Margus B, Berde CB, Yu TW. A framework for individualized splice-switching oligonucleotide therapy. Nature. 2023 Jul;619(7971):828-836. doi: 10.1038/s41586-023-06277-0. Epub 2023 Jul 12. PMID: 37438524; PMCID: PMC10371869.
5. Nakayama, T., El Achkar, C.M., Burbano, L.E. et al. Antisense oligonucleotide-mediated knockdown therapy in two infants with severe KCNT1 epileptic encephalopathy. Nat Med (2026). https://doi.org/10.1038/s41591-026-04314-9
6. Prasad V, Makary MA. FDA’s New Plausible Mechanism Pathway. N Engl J Med. 2025 Dec 11;393(23):2365-2367. doi: 10.1056/NEJMsb2512695. Epub 2025 Nov 12. PMID: 41223362.
7. Cheerie D, Meserve MM, Beijer D, Kaiwar C, Newton L, Taylor Tavares AL, Verran AS, Sherrill E, Leonard S, Sanders SJ, Blake E, Elkhateeb N, Gandhi A, Liang NSY, Morgan JT, Verwillow A, Verheijen J, Giles A, Williams S, Chopra M, Croft L, Dafsari HS, Davidson AE, Friedman J, Gregor A, Haque B, Lechner R, Montgomery KA, Ryten M, Schober E, Siegel G, Sullivan PJ, Whittle EF, Zardetto B, Yu TW, Synofzik M, Aartsma-Rus A, Costain G, Lauffer MC; N=1 Collaborative. Consensus guidelines for assessing eligibility of pathogenic DNA variants for antisense oligonucleotide treatments. Am J Hum Genet. 2025 May 1;112(5):975-983. doi: 10.1016/j.ajhg.2025.02.017. Epub 2025 Mar 25. PMID: 40139194; PMCID: PMC12120168.

Additional Links:

8. Rare therapies and UK regulatory considerations
9. Tim Yu: OTS Pathways for Patient Centered Interventional Genomic Medicine
10. Response to the FDA’s proposed pathway for individualized genetic therapies
11. Julia Vitarello & Timothy Yu – GoldLab Symposium 2019
12. Bold Predictions for Human Genomics by 2030

The clock was ticking as soon as baby KJ was born in the summer of 2024. Within two days of his birth, he was lethargic and struggled to breathe. His blood test results showed elevated ammonia levels, leading to a diagnosis of carbamoyl-phosphate synthetase 1 (CPS1) deficiency. This ultra-rare disease affects around 1 in 1,300,000 individuals, and only half of those born with the disorder will make it beyond early infancy.

As soon as KJ was diagnosed, a team of researchers began developing a bespoke gene editor for him. Within six months, the baby had received two doses of his individualized therapy, and his parents say that every day, he’s showing signs of growing and thriving.

Time was of the essence in creating KJ’s treatment — at five months old, his condition had worsened to the point he was on a list for liver transplantation. Due to this urgency, the Food and Drug Administration (FDA) approved his experimental treatment plan after only one week of review following submission of the Investigational New Drug application.

Now, top officials from the FDA want to make it easier to help future baby KJs. Published in the New England Journal of Medicine, Marty Makary and Vinay Prasad explain a Plausible Mechanism Pathway for approving future personalized gene-editing treatments (1).

Shortly after the NEJM article was published, the FDA released a Draft Guidance Document titled “Considerations for the use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause.” The draft guidance provides greater detail and addresses some concerns raised after the release of the NEJM article.

Five aspects of KJ’s therapy: how the Plausible Mechanism Pathway works

Traditional FDA drug approvals emphasize proven safety and efficacy through phased clinical trials with multiple participants. However, for patients with rare diseases that have a bespoke therapy targeting their unique genetic mutation, assembling enough participants for a randomized controlled trial is unfeasible due to small patient pools.

The new pathway outlined in the NEJM article addresses this limitation by allowing approval based on a plausible-mechanism framework that includes mechanistic evidence plus clinical-course interpretation. Makary and Prasad state that Baby KJ’s story highlights several aspects that define the FDA’s plausible mechanism category. First, there was a specific molecular or cellular abnormality, not a broad diagnostic spectrum. Makary and Prasad state that the FDA will reserve the Plausible Mechanism Pathway for diseases like this, for which the biological cause is known, to “safeguard against misapplication to disparate conditions with similar phenotypes” (1).

Secondly, the NEJM paper states that KJ’s therapy was developed to target the underlying biological alterations, and thirdly, that his care team relied on a well-characterized natural history of the disease, both of which support a reliable interpretation of clinical changes.

In mouse models of Baby KJ’s disease, results showed successful editing in 42% of liver cells. This evidence of target editing, demonstrated in cell or animal models, is listed as the fourth eligibility criterion for a therapy to be included in the Plausible Mechanism Pathway (1).

Finally, they state that the patient must show improvement in clinical outcomes or course. Makary and Prasad clarify that for conditions with progressive deterioration, consistent improvements will be viewed positively by the FDA. For conditions characterized by episodic waxing and waning, the FDA will look for prolonged periods of disease remission (1).

“The FDA will consider previous clinical course and, in some cases, will view patients as their own control,” the authors state in the NEJM article. “Clinical data must be strong enough to exclude regression to the mean” (1).

FDA Draft Guidance: Further Developing the Plausible Mechanism Pathway Framework

Following the NEJM article, the FDA released the much more comprehensive Draft Guidance, which “outlines a set of recommendations to help developers of individualized therapies generate sufficient clinical safety and efficacy data to demonstrate that a drug or biological product is safe and effective for the intended use, and that the product can be manufactured to regulatory quality standards.” The data generated under this framework is then used to support approval or licensure of the therapy for a specific indication.

While the NEJM article uses five aspects from the development of Baby KJ’s therapy to show how the framework would be developed, the Guidance Document provides far greater detail in outlining recommendations. In some recommendations, the FDA Guidance departs from the NEJM article.

Notably, the Guidance explains that approval occurs within existing regulatory approval pathways. Highlighting this, the Guidance references many prior guidance documents to point to existing recommendations, such as those providing recommendations for design of nonclinical POC and safety studies for genome editing (GE) and antisense oligonucleotide (ASO) products, nonclinical recommendations to assess safety of ASOs, ethical considerations for individualized therapies, development of drugs for rare diseases, IND submissions for individualized RNA-targeted therapies, and potency assays for GE products.

The five aspects mentioned in the NEJM article are clearly provided in the FDA Guidance:

“Application of the plausible mechanism framework involves:

• Identifying a specific genetic, cellular, or molecular abnormality with a clear connection between specific alteration and disease indication
• Developing a therapy that targets the underlying or proximate pathogenic biological alterations
• Relying on a well-characterized natural history of the disease in an untreated population
• Confirming that the target was successfully drugged or edited or both
• Demonstrating improvement in clinical outcomes or course.”

The Guidance specifically discusses genetically targeted therapies, including both GE technologies and RNA-targeted therapies, such as ASOs and small interfering RNAs. However, it also allows that the general concepts may apply to other types of individualized therapies.

It outlines the regulatory pathway, goals of nonclinical programs, and opportunities for data leveraging. Then, it separately outlines study and safety assessment recommendations for the FIH trial for Gene Editing products and ASOs, followed by guidance on studies to support approval for each type of therapy.

Under the Clinical section, the Guidance emphasizes safety, planning, and data quality, requiring substantial evidence of effectiveness. “Given the very small number of patients expected to be treated, early planning is critical to identify the potential sources of efficacy and safety data for the product to support a future marketing application. FDA anticipates that the first-in-human clinical investigation that will open an IND will also be the primary source of evidence to support approval; therefore, protocols should be designed to be adequate and well-controlled.”

Timely and urgently needed: potential benefits of the Plausible Mechanism Pathway

The Plausible Mechanism Pathway is mainly for cases like Baby KJ’s, where quick, targeted therapies can be lifesaving. For patients with rare diseases, this path could potentially mean no longer having to wait years for treatment, but only months.

Currently, single patients can receive treatment from investigational therapies in clinical trials under the expanded access, without an expectation that the data be used. In contrast, therapies developed under the plausible mechanism pathway could be used to generate critical clinical safety and efficacy data to be used in developing products that can be modified to address other genetic mutations (1).

Additionally, according to the NEJM article “sponsor will be tasked, as a postmarketing commitment, with collecting real-world evidence to confirm continued preservation of efficacy and to show that there were no off-target edits… as well as to study the effect of early treatment on childhood growth and developmental milestones and to detect unexpected safety signals” (1).

The FDA Guidance clarifies that, “FDA may require that data on safety continue to be collected in the post-marketing setting. This may also include collection of efficacy outcomes if there is evidence of a potential for loss of efficacy over time… FDA also intends to closely monitor reports of adverse events from the trial and any signals of unexpected or delayed adverse events in the post-market setting. If a safety signal emerges, FDA will investigate the signal to determine if any action is warranted.” Further recommendations are also found in existing FDA Guidance documents mentioned previously.

While rare diseases, especially those that are fatal or linked to severe childhood disability, will be prioritized under this pathway, Makary and Prasad say a Plausible Mechanism Pathway will also be available for common diseases, specifically conditions that lack proven alternative treatments or have a large unmet need after trying available therapy (1). “For instance, a single disease with 150 different genetic mutations with the same functional implication may require 150 different therapies, and the Plausible Mechanism Pathway would be ideally suited to such therapies,” they state (1).

In this, the two documents differ. The FDA Guidance narrows the scope to only encompass individualized therapies, going on to definine them as “For the purposes of this guidance, individualized therapies are considered therapies that target a specific pathophysiologic abnormality serving as the root cause of a disease, for example, specific pathogenic genetic variant(s) causing a severely debilitating or life-threatening disease or condition in a small number of patients where a randomized controlled trial typically is not feasible.”

An editorial response to the NEJM article that was published in Molecular Therapy characterizes the pathway as important, timely, and urgently needed (2). Timothy Yu, one of the lead authors of the article, writes that reserving the pathway for interventions grounded in compelling genetic evidence of a correctable mechanism will ensure its integrity. For example, it could apply to “strategies that directly address the primary molecular defect in well-characterized monogenic disorders, such as restoring functional gene expression in a loss-of-function condition, specifically knocking down the expression of a nonessential but toxic gene product, or precisely correcting disease-causing mutations back to wild-type sequences” (2).

Additionally, Yu proposes that sponsors using this pathway should be required to submit data about the manufacturing processes and outcomes to a centralized evidence base, allowing the industry to learn from each treated patient. “Analysis of pooled preclinical, clinical, and post-marketing data will be required to assess overall outcomes, refine regulatory requirements and best practices, assess safety signals, and accelerate collective learning for this new pathway in a responsible manner” (2). Products approved under this framework would have met the same safety and efficacy standards as other FDA-approved therapeutics (2).

The FDA Guidance also emphasizes this, with an entire section on the importance of data sharing, which states, “Shared learning through appropriate data sharing is one opportunity to facilitate continued research.”

“A final imperative is timely development of consistent reimbursement models by payors to ensure equitable patient access and continued investment,” Yu notes. “Fatal or very serious disorders of children are prime candidates for these therapies, and time is of the essence if intervention is to be successful.”

Yu views this new pathway not just as a niche fix, but as a way to advance individualized genetic medicines into routine clinical practice for patients and families affected by these rare conditions worldwide (2).

Unclear criteria and risk of becoming the norm: potential risks and criticisms of the NEJM Article

Enthusiasm for the new pathway is high, and some concerns are not about the plausible mechanism idea but about the approach and how it could be extended beyond narrowly defined cases. While there’s consensus that a new pathway is needed for individualized therapies, some regulatory experts and bioethicists caution that the pathway could be used to push forward treatments with less certain efficacy or those with enough patients for which a rigorous, controlled trial should take place, for the benefit of patients.

Holly Fernandez Lynch, a bioethicist at the University of Pennsylvania and the lead author of an editorial published in Health Affairs Forefront, which responded to Makary and Prasad’s article, explains that the concern is not about the plausible mechanism idea. Instead, one of the bigger concerns is that the fuzzy legal process initially used to announce the pathway may leave it open to legal disagreements with companies that believe they should be eligible for the Plausible Mechanism Pathway.

Additionally, Lynch says, “the concern is that they’ve done it out of compliance with the good guidance practice regulations, which specifically say that if you’re making a substantial change to FDA policy, you cannot announce that to the public for the first time through media interviews and through journal articles, which is exactly what they did here.” Instead, Lynch says a guidance document that would have provided more detail on the pathway’s legal authority should have been created first. Lynch explains that this type of document would’ve informed the regulated community of precise details and given people an opportunity to weigh in.

Lynch also says the criteria of the Plausible Mechanism Pathway are unclear, explaining that Makary and Prasad list out the five characteristics of Baby KJ’s case but do not specify if all five need to be present to meet the requirements.

And then there are the scope concerns, and the risk of approving therapies that seem promising in theory but fail in practice. She explains that the drug Sarepta — approved for treating Duchenne muscular dystrophy — is one such example. Despite Sarepta having four drugs approved for the disease, all with a plausible mechanism, none have shown any clinical benefit in clinical trials, and one recent trial testing two of the drugs demonstrated little difference between placebo and treatment.

“We know that when the FDA opens the door to these things, there’s a lot of pressure … to then open the door a little wider and then a little wider and then a little wider until you have an exceptional program becoming the norm,” says Lynch. “These are desperate disease areas, and so sponsors and patient groups are going to be grasping at anything that could be beneficial to them here.”

This has happened before: in 1992, the FDA dismissed concerns that a new accelerated approval pathway designed for getting drugs to dying AIDS patients more quickly would become the norm for drug approval. Now, nearly a third of oncology drugs are approved this way, many of which have not demonstrated an improved survival rate.

Additionally, Makary and Prasad write about expanding the pathway beyond cases like Baby KJ, and Lynch questions what the limits would then be. She argues that it should apply only when a traditional randomized trial is not feasible, keeping it as close as possible to an n-of-1 or n-of-a-few design. “The concern is: How strictly are those characteristics or requirements going to be interpreted once FDA rolls this out? How strict are they going to be about confirming that the target was successfully drugged, or improvement in clinical outcomes?”

Yet others see it as being clearly “designed to evaluate personalized, N=1 therapies—treatments so individualized that traditional randomized controlled trials are impossible.” This editorial goes on to state that “the PMP is intentionally narrow and relies on biological clarity… is not intended for common or biologically complex diseases.”

The FDA Guidance document addresses many of these concerns, and the FDA is accepting comments on the Draft Guidance through April 27, 2026, allowing stakeholders to provide the necessary input.

Future of the Plausible Mechanism Pathway

The fast approval of Baby KJ’s therapy likely saved the infant’s life. While researchers are still in the early stages of understanding the extent to which his bespoke therapy has benefited him, he will likely live with a milder form of his disease. The Plausible Mechanism Pathway aims to drastically shorten development timelines for future individualized medicines, providing hope for patient populations that typically have no treatment options.

However, Prasad and Makary caution that disciplined implementation will be imperative to the pathway’s success. By prioritizing mechanisms over outcomes, there is a risk of approving therapies that seem promising in theory but fail in practice. Additionally, without data from randomized control trials, it’s harder to assess the true benefits versus placebo effects or natural disease progression. As Lynch noted, there is potential for companies to pressure the FDA to accept drugs that don’t necessarily fit the pathway’s mould, and for that to become the norm.

This tension over evidentiary standards and regulatory flexibility has come into sharper focus amid recent leadership changes at the agency: on March 6, it was announced that Prasad would be stepping down as director of the FDA’s Center for Biologics Evaluation and Research. Prasad’s departure follows criticism from the biotech and pharmaceutical industries, which have accused the FDA of reversing previous guidance on the evidence they can use to support their applications. In the past year, the agency has rejected or deferred approval for at least eight drugs for rare diseases, citing issues with the data companies provided to support their applications. However, this has raised questions about how consistently the FDA applies the regulatory flexibility it promotes.

As for the plausible mechanism pathway, the Prasad and Makary article states that the FDA is always open to additional feedback and suggestions regarding it. “Meanwhile,” they state, “for patients and families, there is no time to wait.”

The swift release of the FDA Draft Guidance and commentary in its press release supports this view. “We anticipate our Plausible Mechanism draft guidance will inspire industry to place increased focus on individualized therapies, thereby driving innovation, improving safety, lowering costs and offering more patients with ultra-rare diseases a unique shot at a life-saving treatment.”

References:

1. Prasad V, Makary MA. FDA’s New Plausible Mechanism Pathway. N Engl J Med. 2025 Dec 11;393(23):2365-2367. doi: 10.1056/NEJMsb2512695. Epub 2025 Nov 12. PMID: 41223362.
2. Yu TW, Vitarello J, Musunuru K, Ahrens-Nicklas RC, Liu DR, Mellion ML, Urnov F, Yan W, Chunduru S, Barrett D, Flotte TR, Woodcock J. Response to the FDA’s proposed pathway for individualized genetic therapies. Mol Ther. 2026 Jan 7;34(1):1-2. doi: 10.1016/j.ymthe.2025.12.032. Epub 2025 Dec 29. PMID: 41468889.
3. FDA Draft Guidance: Considerations for the use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause. 2026 Feb 25.

Disclaimer:

“The views, opinions, findings, and conclusions or recommendations expressed in these articles and highlights are strictly those of the author(s) and do not necessarily reflect the views of the Oligonucleotide Therapeutics Society (OTS). OTS takes no responsibility for any errors or omissions in, or for the correctness of, the information contained in these articles. The content of these articles is for the sole purpose of being informative and is not intended as an endorsement of any company, technology, or therapeutic that is mentioned. The content is not and should not be used or relied upon as medical, legal, financial, or other advice. Nothing contained on OTS websites or published articles/highlights is intended by OTS or its employees, affiliates, or information providers to be instructional for medical diagnosis or treatment. It should not be used in place of a visit, call, consultation, or the advice of your physician or other qualified health care provider. Always seek the advice of your physician or qualified health care provider promptly if you have any healthcare-related questions. You should never disregard medical advice or delay in seeking it because of something you have read on OTS or an affiliated site.”

Date: September 24, 2026
Time: 11-12pm EDT / 5-6pm CEST

Title: Immunogenicity Risk Assessment for Nucleic Acid Therapeutics: A Comprehensive Evaluation for ASO, siRNA, and Nonvaccine mRNA/LNP Therapies

Description:

Nucleic acid therapeutics require new immunogenicity evaluation frameworks, as the safety and efficacy of these therapies can be impacted by immune responses triggered by different molecular components of these drugs (ASO, siRNA, and non-vaccine mRNA/LNP). This webinar will cover recommendations on conducting immunogenicity risk assessments and developing the right monitoring strategies to get these therapies safely to patients.

Speaker:

Date: September 17, 2026
Time: 11-12pm EDT / 5-6pm CEST

Title: Streamlining Exon-Skipping Antisense Oligonucleotide Therapy Development Via a High-Throughput Approach

Description:

Disease-modifying therapies are available for <5% of the >7000 described rare genetic diseases (RGDs). Antisense oligonucleotides (ASOs) represent a promising precision therapy platform for novel RGD therapies, with a leading approach being ASO-mediated ‘skipping’ of an exon containing a deleterious variant to rescue protein function. However, major challenges in this field are that comprehensive analyses identifying exons amenable to ASO-mediated skipping are non-existent, and patient identification and ASO design remain reactive and slow processes. We therefore sought to proactively identify skippable exons across the genome and design ASO sequences that target these exons, shared as an open-access resource.

Speaker:

Hailey was born a healthy baby, her mom says, hitting all her infant milestones like rolling over and sitting up. But at nine months old, she began falling over when she sat up and having constipation and little sleep. Her concerned mom brought it up at a pediatric appointment, but she was dismissed as being a nervous first-time parent. Four months later, the little girl had her first grand mal seizure. These seizures, along with a failure to thrive and her other initial symptoms, continued. At 16 months, she took her first steps but was always falling and was behind on her speech and other milestones. At 23 months, Hailey had a 90-minute seizure and was airlifted to a children’s hospital. After an MRI and blood tests, the doctors declared her fine. It wouldn’t be until Hailey was six that she finally received a diagnosis of Alexander disease, a rare neurological condition.

Previously, no drugs existed that could change the course of the disease, and treatments focused on managing symptoms. However, Ionis Pharmaceuticals’ therapy, called zilganersen, recently received a breakthrough therapy designation from the Food and Drug Administration (FDA), based on encouraging clinical trial results of patients with Alexander disease.

Alexander Disease: rare, progressive, and fatal

Alexander disease is an ultra-rare, progressive neurological disorder that causes severe disability and death. The disorder is estimated to occur in around one in one to three million people worldwide. Symptoms can first appear in newborns or at any time throughout childhood and into young adulthood, with most children displaying symptoms by age four. An earlier onset typically means a more severe disease and a less likely outcome of surviving past adolescence. If the onset occurs after the age of four, symptoms may be less severe and progress more slowly. While it’s rare, older adults can also be diagnosed with Alexander disease, usually with milder symptoms.

Seizures, muscle stiffness (especially an inability to control muscles for swallowing, airway protection, and purposeful movements), and developmental delays are hallmark symptoms of the disease, which can also cause an enlarged brain and/or head, hydrocephalus, feeding problems, and sleep disorders, depending on the age of onset. The disease usually leads to death within 14-25 years after symptom onset. Classified as a leukodystrophy, a group of genetic conditions that affects the brain’s white matter, Alexander disease can be further categorized as a neurodegenerative leukodystrophy, meaning that over time, neurons lose their structure and functionality.

The disease is typically caused by mutations in the GFAP gene on chromosome 17, leading to an overproduction of an abnormal form of glial fibrillary acidic protein (GFAP). The excess GFAP then causes protein clumps to form in the arms of astrocytes, which are specialized glial cells in the central nervous system. These protein clumps, known as Rosenthal Fibers, may accumulate in the cerebral cortex, white matter of the brain, brainstem, and spinal cord, ultimately causing progressive damage to the nervous system and the symptoms of Alexander disease.

In Hailey’s case, when she was five, she had learning disabilities, speech delays, was unable to walk far, and had an abnormally big head. Around this time, doctors tested her for leukodystrophy, but the results were negative. However, a young doctor became Hailey’s neurologist and was determined to find a diagnosis. She was signed up for a study on children with epilepsy, which included a brain MRI, and she was also tested for Alexander disease.

A combination of clinical presentation, brain magnetic resonance imaging (MRI) findings, and genetic testing is used to diagnose the disease. Interventions, including physiotherapy, speech therapy, nutrition, and anti-epileptic drugs, can help manage symptoms as the disease progresses. But before zilganersen — an antisense oligonucleotide therapy that blocks the excess production of GFAP caused by a mutation in the GFAP gene  — no treatments existed that actually aimed to stop the accumulation of the damaging protein.

The global trial and results: statistically significant and clinically meaningful

The breakthrough therapy designation was granted based on results from a phase 1-3 multiple ascending dose study that assessed the safety and efficacy of zilganersen in 54 participants aged 1.5 to 53 years with genetically confirmed Alexander disease. The participants, most of whom were children, were randomly assigned 2:1 to receive either 25mg or 50mg of zilganersen or placebo via intrathecal bolus (ITB) once every 12 weeks for a 60-week double-blind treatment period. After the 60-week double-blind period, participants transitioned into open-label treatment, followed by a 120-week long-term extension phase, in which those receiving the 25 mg dose began receiving 50 mg.

Results of the global trial, which took place across 13 sites in eight countries, showed that those receiving the 50mg dose of zilganersen had a statistically significant and clinically meaningful improvement from baseline in gait speed compared to placebo at week 61, as assessed by the 10-meter walk test, which found a mean improvement of 33% in patients given the higher dose. The results also demonstrated consistent favorable trends across key secondary endpoints, including patient- and clinician-reported measures that indicate slowed disease progression, stabilization, or improvement. The therapy was safe and well-tolerated, with most adverse events being mild or moderate. Serious adverse events occurred less often in the zilganersen group than in the placebo group.

“People living with Alexander disease have gone far too long without a treatment capable of changing the course of their disease, which makes this Breakthrough Therapy designation particularly meaningful,” said Holly Kordasiewicz, PhD, Executive Vice President, Chief Development Officer at Ionis, in a press statement. “Our pivotal zilganersen study provides the first evidence that an investigational treatment can modify the underlying disease and improve outcomes, representing an important step forward for the Alexander disease community.”

An open-label sub-study for patients under age two continues, and enrolled participants can access zilganersen in the long-term extension.

Previous trial and FDA designations

In 2020, zilganersen was granted Orphan Drug designation and Rare Pediatric designation by the U.S. Food and Drug Administration (FDA). Additionally, in 2019, the European Medicines Agency (EMA) granted zilganersen an Orphan Drug designation.

In 2021, Ionis Pharmaceuticals successfully treated rats exhibiting features of Alexander disease with zilganersen. The study found that rats treated at three weeks old, before the onset of noticeable symptoms, were physically indistinguishable from normal rats. The group that was treated at eight weeks old, when severe impairment was present, had the Rosenthal fibres disappear within a few weeks after one injection, and several disease markers returned to levels close to normal (1).  The encouraging results of this study enabled Ionis to continue on to the recent clinical trial.

Future of zilganersen and those with Alexander disease

After Hailey received the diagnosis, she continued to attend school with the help of an aide. Recently, the now 20-year-old graduated from high school.

“Hailey loves to draw in her sketchbook, enjoys watching cooking shows, and wants to be a chef when she grows up,” her mom says. “She has quite a collection of Barbie dolls, loves the color pink, shopping, and trying new restaurants.”

Despite this, the young woman still has significant learning disabilities, struggles to walk, and has a speech that is difficult to understand, her mom says.

“A treatment could mean Hailey could stay stable, or perhaps it might get her walking better and not need her wheelchair,” her mom says. “I believe it will happen and increase her quality of life.”

The breakthrough therapy designation is a positive step forward for patients like Hailey and their families, with zilganersen providing a potential treatment for not just managing symptoms, but changing the course of their disease. According to the company, Ionis plans to file a new drug application in the early months of 2026 and is working to initiate an expanded patient access program in the U.S.

References:

1. 1. Hagemann TL, Powers B, Lin NH, Mohamed AF, Dague KL, Hannah SC, Bachmann G, Mazur C, Rigo F, Olsen AL, Feany MB, Perng MD, Berman RF, Messing A. Antisense therapy in a rat model of Alexander disease reverses GFAP pathology, white matter deficits, and motor impairment. Sci Transl Med. 2021 Nov 17;13(620):eabg4711. doi: 10.1126/scitranslmed.abg4711. Epub 2021 Nov 17. PMID: 34788075; PMCID: PMC8730534.

“The views, opinions, findings, and conclusions or recommendations expressed in these articles and highlights are strictly those of the author(s) and do not necessarily reflect the views of the Oligonucleotide Therapeutics Society (OTS). OTS takes no responsibility for any errors or omissions in, or for the correctness of, the information contained in these articles. The content of these articles is for the sole purpose of being informative. The content is not and should not be used or relied upon as medical, legal, financial, or other advice. Nothing contained on OTS websites or published articles/highlights is intended by OTS or its employees, affiliates, or information providers to be instructional for medical diagnosis or treatment. It should not be used in place of a visit, call, consultation, or the advice of your physician or other qualified health care provider. Always seek the advice of your physician or qualified health care provider promptly if you have any healthcare-related questions. You should never disregard medical advice or delay in seeking it because of something you have read on OTS or an affiliated site.”

Date: June 18, 2026
Time: 11-12pm EDT / 5-6pm CEST

Title: Advancing Precision Medicine: Oligonucleotide Therapeutics and Genome Editing

Description:

The advent of programmable therapeutics — from oligonucleotide drugs to genome editing technologies — is transforming the treatment landscape for genetic and acquired diseases. The talk will discuss recent advances in antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and genome editing technologies, as well as the design of delivery systems tailored for tissue-specific targeting and intracellular trafficking. Through selected case studies and pipeline insights, this seminar will highlight how cutting-edge genome editing and oligonucleotide technologies are converging to realize the full promise of precision medicine — enabling disease-modifying treatments across a spectrum of indications.

Speaker:

When Julie was just 18, her blood results revealed alarmingly high triglyceride levels at over 1,000 mg/dL. Two years later, she had her first acute pancreatitis attack. Although she would suffer from monthly pancreatitis flares after having her son and her triglycerides would escalate to over 10,000 mg/dL, she wouldn’t receive a diagnosis of familial chylomicronemia syndrome (FCS) for years.

For too long, FCS has been an untreatable condition, but the past few years have seen landmark advancements in treatment options. Recently, the U.S. Food and Drug Administration (FDA) approved Redemplo (plozasiran) for the treatment of adults with familial chylomicronemia syndrome (FCS). Redemplo was approved only a year after the approval of Tryngolza (olezarsen) in late 2024.

Familial Chylomicronemia Syndrome: rare and misdiagnosed

Familial chylomicronemia syndrome (FCS) — also known as lipoprotein lipase deficiency — is a rare, inherited disease that impairs the body’s ability to metabolize fats. Those with FCS lack functional lipoprotein lipase (LPL), the enzyme needed for breaking down fats, thus impeding the body’s ability to eliminate triglycerides from the bloodstream. Normal triglyceride levels are below 150 mg/dL, but people with FCS have levels that can far surpass 880 mg/dL.

About 80% of familial hyperchylomicronemia syndrome is due to inherited defects in both alleles of the lipoprotein lipase gene. The remaining 20% is attributable to other genetic mutations affecting lipoprotein lipase function, such as apolipoprotein C-II (APOC2), apolipoprotein A-V (APOA5), high-density lipoprotein binding protein 1 (GP1HBP1), and lipase maturation factor 1 (LMF1). All these mutations lead to the malfunctioning of the lipoprotein lipase enzyme (1).

Affecting one to ten people per million worldwide, the disorder significantly increases the risk of acute pancreatitis, a painful and potentially fatal swelling of the pancreas. Acute severe pancreatitis can also cause multi-organ failure and increase morbidity and mortality, as well as lead to chronic pancreatitis (1). These attacks often happen repeatedly, requiring multiple hospital visits.

The disease is often misdiagnosed as it shares symptoms with more common conditions, like multifactorial syndrome or MCS. Key indications of FCS are chronic fatigue, forgetfulness, spleen and liver swelling, and fatty deposits known as xanthomas that build up in the skin, especially in the arms, buttocks, and/or knees. The disease’s psychological and financial burden has also contributed to patients reporting feelings of anxiety, isolation, and depression. Additionally, hypertriglyceridemia is an independent risk factor for cardiovascular diseases and other complications, including changes in mental activity, loss of memory, and difficulty concentrating (1).

Dr. Christie Ballantyne, chief of cardiovascular research at Baylor College of Medicine and principal investigator of the PALISADE trial for Redemplo, explained in an HCP Live interview that diagnosis relies on integrating genetic testing with structured clinical evaluation. He said that diagnosis is rarely based on a single finding, but rather on a coordinated interpretation of laboratory results, clinical history, and genetic data, adding that this approach speeds up referrals to lipid specialists and ensures that patients who qualify for newly approved therapies are identified efficiently.

Prior to the approval of Redemplo and Olezarsen, the only treatment options for those with FCS were to follow a highly fat-restricted diet, exercise, and eliminate alcohol and simple carbohydrates, and those in the EU have been able to receive Volanesorsen since 2019. Even with the lifestyle changes, Ballantyne said, it is still difficult for those with FCS to lower their triglycerides.

“It was frustrating that there was a genetic disorder that we simply could not treat,” he said.

Ballantyne suggested that the lipid profile of anyone with pancreatitis should be checked, and that high triglycerides are a red flag for FCS. When triglycerides are over 880, patients have chylomicrons, large particles full of triglycerides from the diet, which doctors should recognize as a risk for pancreatitis.

In Julie’s case, after giving birth, she was hospitalized every month for two years due to her pancreatitis episodes. She was missing precious moments with her infant son and husband. Looking for answers, she underwent multiple surgeries over the next seven years, including a radical hysterectomy at 34 that would prevent her from having the large family she dreamed of. Still no diagnosis. No answers.

During a plasma exchange, a practitioner noticed chylomicrons in Julie’s blood. She went home, researched the terms, and found information about FCS, which she brought to her lipidologist. Three months later, she was finally diagnosed with FCS.

PALISADE trial: lower triglycerides and reduced risk of pancreatitis

The approval of Redemplo, announced on November 18, 2025, marks Arrowhead Pharmaceuticals’ first FDA-approved therapy. In January 2025, the FDA accepted Redemplo’s New Drug Application (NDA) based on results from its PALISADE phase 3 trial, and supportive data from its phase 2 SUMMIT program.

In the press release, Christopher Anzalone, Ph.D., President and CEO at Arrowhead Pharmaceuticals, said that “The FDA approval of REDEMPLO is a transformational milestone for Arrowhead. This is a proud moment for all those involved in the discovery and development process and represents new hope for the estimated 6,500 people in the U.S. living with genetic or clinical FCS. This approval, and subsequent launch, marks the beginning of a new chapter in our journey—one rooted in our unwavering commitment to delivering life-changing therapies to patients with serious diseases.”

Redemplo is a small interfering ribonucleic acid (siRNA) conjugated with N-acetylgalactosamine (GalNAc) for targeted liver delivery. Redemplo is approved as an adjunct to diet and is administered as a subcutaneous injection once every three months, which can be done at home.

It acts by suppressing the production of a specific protein called apolipoprotein C-III (APOC3), a significant component of triglyceride-rich lipoproteins (TRLs) that also regulates triglyceride metabolism. As triglyceride blood levels rise, APOC3 prevents the breakdown of TRLs by lipoprotein lipase and the uptake of TRL remnants by hepatic receptors in the liver (1). By reducing APOC3 levels, TRL clearance increases, resulting in lower blood triglyceride concentrations.

Participants in the PALISADE trial included patients who had a fasting triglyceride level of ≥880 mg/dL and a diagnosis of FCS who were willing to follow dietary counselling and local standard of care. A total of 75 participants from 18 countries were enrolled in the trial and randomly assigned to receive 25 mg or 50 mg of plozasiran, or a matching placebo, all administered once every three months for 12 months (1). The primary endpoint was the median percent change from baseline in fasting triglycerides at month 10. Secondary endpoints included incidence of acute pancreatitis, the percent change from baseline to mean values of fasting triglycerides at months 10 and 12, as well as percent changes in apoC-III and non-HDL-C at months 10 and 12 (2).

Results showed that at 10 months patients receiving the 25 mg dose had a median change in the fasting triglyceride level as compared with placebo of -59 percentage points, while the 50-mg plozasiran group had a change of -53 percentage points. Additionally, the pooled 25 mg and 50 mg group had an 83% lower risk of acute pancreatitis compared with the placebo group. These triglyceride drops were seen as early as one month and persisted throughout the 12 months. A favorable tolerability profile was observed throughout the trial, and the most common adverse reactions were hyperglycemia, headache, nausea, and injection site reaction.

Lindsey Sutton Bryan, co-founder and co-president of the FCS Foundation, said that the approval of Redemplo marks a pivotal moment for people living with familial chylomicronemia syndrome and the physicians who support them.

“Because FCS symptoms are mostly invisible, this community historically has been often overlooked and misunderstood, making their journey to effective treatment especially difficult,” she said.

Plozasiran is also being investigated in multiple SHASTA Phase 3 studies in patients with severe hypertriglyceridemia, as well as the MUIR Phase 3 study in patients with mixed hyperlipidemia. It has also been submitted to additional global regulatory authorities for review and marketing authorization.

Volanesorsen and Olezarsen: reduce triglycerides and lower the risk of pancreatitis

The first drug approved to treat FCS was Waylivra (Volanesorsen) by Ionis and Akcea, which was approved by the European Medicines Agency in 2019. It is a second-generation 2′-O-methoxyethyl (2′-MOE) ASO that blocks the production of apoC3 by targeting mRNA. After three months in the phase 3 study, participants had a 77% mean percentage change in triglyceride levels, compared with an 18% increase found in the placebo-receiving control group, although reduced platelet counts were a common side effect (3).

The second FCS treatment to receive regulatory approval was olezarsen (TRYNGOLZA), an antisense oligonucleotide (ASO) conjugated with GalNAc for liver targeting. The drug, approved by the US FDA in 2024, binds to and promotes the degradation of apoC3 mRNA via RNase H-mediated cleavage (4), distinct from the RNA interference mechanism used by siRNAs like Redemplo. Both ASO and siRNA therapies target apoC3 to reduce triglycerides in FCS, but they employ different RNA-targeting modalities.

Their administration frequencies differ as well, with Redemplo given every three months and Olezarsen administered once a month, while Waylivra is administered once a week for three months, then reduced to once every two weeks. Like Redemplo, however, Olezarsen and Waylivra successfully lowered triglyceride levels and reduced the risk of pancreatitis in the patients participating in their trials.

The future of FCS treatment

For those newly diagnosed with FCS, Julie said to give yourself grace. “Find your support system—family, friends, online communities. You are not alone. This disease does not define you. You can still have dreams and goals. Make plans, be flexible with adjustments, but don’t stop dreaming.”

25 years into her own health journey, Julie is still dreaming. “Having a triglyceride level under 500 makes me a little giddy. It’s exciting to think about that possibility. Fewer hospitalizations would mean everything to me. I could live. I could plan for my future… It would mean possibility.”

Ballantyne said that both Redemplo and Tryngolza have dramatically altered treatment options for patients with FCS, although it’s essential for people on these therapies to maintain a low-fat diet to benefit from lower triglycerides and reduced risk of pancreatitis.

“The dietary part is still important,” he said. “But it used to be that with the diet, they [FCS patients] couldn’t get their numbers very low. Now if they take the medication on time and follow the diet, they can get themselves in a safe zone where they’re not at risk of pancreatitis.”

“These therapies work,” he added. “Patients who [triglycerides] could not be controlled can now be controlled.”

The recent approvals of Redemplo and Tryngolza signal a new era for people living with FCS — one in which pancreatitis is no longer an inevitable outcome and triglyceride levels can finally be brought under control. For patients like Julie, these therapies offer not just clinical improvement but the chance to reclaim time, energy, and milestones once overshadowed by hospitalization and uncertainty. As awareness grows, specialists will more readily recognize the signs of FCS, and more patients can be accurately diagnosed and connected with effective treatment sooner. While careful dietary management and lifestyle changes will remain essential, the combination of these new targeted therapies with comprehensive care offers real hope that FCS may become a manageable condition rather than a life-defining burden.

^References:

1. Regmi M, Rehman A. Familial Hyperchylomicronemia Syndrome. 2023 Aug 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. PMID: 31869119.
2. Watts GF, Rosenson RS, Hegele RA, Goldberg IJ, Gallo A, Mertens A, Baass A, Zhou R, Muhsin M, Hellawell J, Leeper NJ, Gaudet D; PALISADE Study Group. Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk. N Engl J Med. 2025 Jan 9;392(2):127-137. doi: 10.1056/NEJMoa2409368. Epub 2024 Sep 2. PMID: 39225259.
3. Witztum JL, Gaudet D, Freedman SD, Alexander VJ, Digenio A, Williams KR, Yang Q, Hughes SG, Geary RS, Arca M, Stroes ESG, Bergeron J, Soran H, Civeira F, Hemphill L, Tsimikas S, Blom DJ, O’Dea L, Bruckert E. Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome. N Engl J Med. 2019 Aug 8;381(6):531-542. doi: 10.1056/NEJMoa1715944. PMID: 31390500.
4. Oligonucleotide Treatment Advances Offer Relief for Patients with Familial Chylomicronemia Syndrome. Oligonucleotide Therapeutics Society. 2025 Feb 5.

Disclaimer:

“The views, opinions, findings, and conclusions or recommendations expressed in these articles and highlights are strictly those of the author(s) and do not necessarily reflect the views of the Oligonucleotide Therapeutics Society (OTS). OTS takes no responsibility for any errors or omissions in, or for the correctness of, the information contained in these articles. The content of these articles is for the sole purpose of being informative and is not intended as an endorsement of any company, technology, or therapeutic that is mentioned. The content is not and should not be used or relied upon as medical, legal, financial, or other advice. Nothing contained on OTS websites or published articles/highlights is intended by OTS or its employees, affiliates, or information providers to be instructional for medical diagnosis or treatment. It should not be used in place of a visit, call, consultation, or the advice of your physician or other qualified health care provider. Always seek the advice of your physician or qualified health care provider promptly if you have any healthcare-related questions. You should never disregard medical advice or delay in seeking it because of something you have read on OTS or an affiliated site.”

Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are uniquely suited to address single-gene diseases affecting skeletal and cardiac muscles. While distributed broadly, they are more likely to accumulate in the liver and kidneys than muscles, thus limiting their treatment applicability. Additionally, the anticipated dose levels needed for unconjugated ASOs to reach these muscles are very high. Ionis Pharmaceuticals, in partnership with Bicycle Therapeutics, aims to change this.

The companies recently published a study in Nucleic Acids Research, demonstrating a delivery method that requires a small dose and improves the potency of oligonucleotide therapeutics for skeletal and cardiac muscle. This work was awarded the OTS Late Discovery Featured Paper of the Year.

Reaching muscle cells: the challenge and the solution

To be effective in muscle, ASOs and siRNAs must travel from the injection site to their RNA target, passing through the bloodstream, crossing capillaries’ endothelium, reaching the tissue interstitium, and finally entering muscle cells (1). In organs like the liver or kidney, the blood vessel walls have larger openings, making it easy for ASOs to slip through. However, in muscle and heart tissue, the capillaries are tightly sealed, creating a significant barrier to drug entry (1).

Transferrin receptor 1 (TfR1) is a highly recycling receptor expressed on the surface of muscle, cardiac muscle, and endothelial cells, where its primary role is iron uptake. Previous studies have shown that attaching an antibody fragment to TfR1 enhances the activity of siRNA and ASOs in mice, demonstrating the potential for delivering oligonucleotide drugs to skeletal muscle (2, 3). However, using antibodies (mAb) and their fragments (Fab) for this purpose presents several challenges: potential off-target effects like anemia and TfR1 depletion caused by anti-TfR1 antibodies (4, 5); the complex structure of antibodies complicates manufacturing (6, 7); their large size requires administering larger volumes, which may reduce tolerability and increase the risk of anti-drug antibody production; and the necessity for intravenous delivery (1, 8).

Bicycle molecules are peptides that possess attractive drug-like properties, such as high affinity and selectivity for their target, high plasma stability, tunable pharmacokinetics, and a more straightforward manufacturing process (1). Unlike conventional small molecules, Bicycle molecules can be readily conjugated to other chemical payloads without losing their pharmacology, states Bicycle Therapeutics. The study uses these peptides as part of Ionis’s broader Ligand-Conjugated Antisense (LICA) strategy, which attaches targeting ligands to ASOs to enhance uptake into specific tissues. The Bicycle approach represents the newest addition to this LICA platform.

Michele Carrer, Ph.D., one of the lead authors of the paper, explained at the 2025 Oligonucleotide Therapeutics Society Annual Meeting that attaching ASOs and siRNAs to a high-affinity bicyclic peptide targeting TfR1 significantly increases their potency in skeletal and cardiac muscles. By linking the two, it naturally guides the antisense molecule into the cell (1).

Bicycle peptide enhances ASO activity in skeletal and cardiac muscle

To demonstrate that the bicycle-based delivery method could work in humans, the researchers created a mouse model expressing the human TfR1 open reading frame. Before selecting BCY17901 as the lead ligand, the team systematically screened 12 different Bicycle peptides with varying TfR1 affinities. By comparing these ligands head-to-head, they identified BCY17901 as the optimal balance of potency, receptor affinity, and intracellular release (1).

They then conjugated these different bicycle molecules to two ASOs: one targeting the Dmpk mRNA and the other targeting the Malat1 RNA. The mice were given either a high dose of the unconjugated ASO, a much lower dose of the Bicycle-ASO, or a benchmark ligand for comparison. After dosing, the researchers measured the extent to which the target gene was reduced in the quadricep muscles and the heart (1).

The results found that, despite being a 10-fold lower dose, the Bicycle ligand (BCY17901) made the ASOs much more effective, achieving more gene knockdown than the high-dose plain ASO in both the quadriceps and heart. When the same Bicycle-ASO was used in normal mice — with mouse TfR1 — delivery was significantly reduced, demonstrating its selectivity to human TfR1 (1).

Bicycle peptide shows robust knockdown, improved potency in muscle cells

To compare the potency of the Bicycle conjugate with that of the unconjugated ASO or lipid-conjugated siRNA molecules, the researchers performed dose-response experiments in mice. In multiple muscle types, the team measured a robust increase in potency for both the Dmpk and Malat1 Bicycle-conjugated ASOs compared to the respective unconjugated ASOs. Additionally, the bicycle conjugates had much lower ED50 values, meaning they required smaller doses to achieve the same effect as the unconjugated ASO (1).

The authors note that the administration of BCY17901-conjugated Malat1 ASO in the mice did not result in target RNA knockdown in the central nervous system, suggesting it did not cross the blood-brain barrier (1).

The researchers also measured how the Bicycle-based conjugates affected the liver. A key nuance is that ASOs and siRNAs behave differently when conjugated to the Bicycle ligand. For ASOs, BCY17901–Malat1 was only slightly more active in the liver relative to the unconjugated ASO. By contrast, for siRNAs, BCY17901–HPRT produced a 5.9-fold decrease in potency in the liver compared to a lipid (palmitate)-conjugated siRNA benchmark. In a separate study, a comparison with a benchmark TfR1-binding antibody fragment (OKT9 Fab’) highlighted this. The antibody fragment drove nearly 90% knockdown in the liver, while the Bicycle–siRNA produced only 43%, demonstrating the clear liver-sparing advantage of small Bicycle ligands over antibody-based systems (1).

Bicycle peptide shows good target knockdown in skeletal and heart muscles of NHPs

The study also demonstrated that Bicycle-conjugated ASOs and siRNAs could efficiently reduce their target RNAs in the skeletal and cardiac muscles of non-human primates (NHPs) (1).

“Of note, BCY17901 has ~ tenfold lower affinity for the cynomolgus monkey TfR1 compared to the human receptor,” the authors state (1).

Despite this lower affinity, conjugation of Malat1 ASO and HPRT siRNA to BCY17901 resulted in 71% and 86% target RNA knockdown, respectively, in quadricep muscles. In the heart, these Bicycle conjugates caused 63% and 75% target reduction, respectively. As seen in mice, conjugation of HPRT siRNA to BCY17901 exhibited a partial liver-sparing effect, resulting in only 11% target knockdown in hepatic tissue (1).

Advantages of Bicycle-ASO conjugates

The Bicycle peptides are well-suited for conjugation to ASOs and RNAs compared to antibody ligands, Carrer explained at OTS 2025.

The Bicycle peptides are also stable and chemically flexible, offering improved tissue penetration, potential lower total drug doses, reduced liver uptake, and easier manufacturing, and are broadly compatible with ASOs and siRNAs (1).

“Their small size potentially enables a lower total dose of drug that needs to be administered to patients,” Carrer said.

Compared to the unconjugated Dmpk ASO, the Bicycle conjugate was 4.9-fold more potent in the quadriceps muscle and 5.8-fold more potent in the gastrocnemius muscle. In the heart, the bicycle ASO achieved a 50% reduction in the target mRNA at a much lower dose than the unconjugated ASO, which was less effective (1).

Limitations and unresolved questions

The authors note that their work has limitations and unanswered questions. Given that TfR1 is expressed in both endothelial and muscle cells, the Bicycle LICA system potentially offers the opportunity to enhance the drug in two ways: helping it cross from the blood into the muscle, and helping muscle cells absorb the drug more easily. However, they haven’t yet quantified the extent to which these two effects contribute to the drug’s overall success (1).

“Furthering the understanding of when the ON [oligonucleotide] cargo dissociates from the Bicycle component of the LICA molecule in the different cell types (e.g. endothelial cells, myofibers, and cardiomyocytes) and in different intracellular compartments will also be instrumental,” the authors state (1).

Also noteworthy and a point of caution, according to the authors, is the difference between the human and mouse heart. In mice, some heart cells may contain the Dmpk gene but not TfR1 (1), “therefore, potentially reducing the efficacy of a TfR1 LICA approach in the mouse cardiac tissue” (1), making the treatment appear less effective in mice than it would hypothetically be in humans.

Future of Bicycle Technology

The study demonstrates that this TfR1-binding Bicycle platform unlocks potent, muscle-specific oligonucleotide delivery, and has the potential to achieve therapeutic-level knockdown at clinically feasible doses, and builds on Ionis’s work to conjugate molecules to ASOs to deliver their drugs to more targets. Going forward, Carrer believes the bicycle conjugates will fit nicely into Ionis’ pipeline, noting that their versatility allows them to work with a wide range of targets.

“The bicycle technology really now opens the door to potentially new medicine that could treat these devastating diseases that affect the skeletal muscle and heart,” Carrer said.

References:

1. Michael E Østergaard, Michele Carrer, Brooke A Anderson, Megan Afetian, Mohsen A Bakooshli, Jinro A Santos, Stephanie K Klein, Juliana Capitanio, Graeme C Freestone, Michael Tanowitz, Rodrigo Galindo-Murillo, Hans J Gaus, Chrissa A Dwyer, Michaela Jackson, Paymaan Jafar-nejad, Frank Rigo, Punit P Seth, Katherine U Gaynor, Steven J Stanway, Liudvikas Urbonas, Megan A St. Denis, Simone Pellegrino, Gustavo A Bezerra, Michael Rigby, Ellen Gowans, Katerine Van Rietschoten, Paul Beswick, Liuhong Chen, Michael J Skynner, Eric E Swayze, Conjugation to a transferrin receptor 1-binding Bicycle peptide enhances ASO and siRNA potency in skeletal and cardiac muscles, Nucleic Acids Research, Volume 53, Issue 7, 24 April 2025, gkaf270, https://doi.org/10.1093/nar/gkaf270
2. Sugo T, Terada M, Oikawa T et al. Development of antibody–siRNA conjugate targeted to cardiac and skeletal muscles. J Control Release 2016; 237 :1–13. https:// doi.org/ 10.1016/ j.jconrel.2016.06.036
3. Malecova B, Burke RS, Cochran M et al. Targeted tissue delivery of RNA therapeutics using antibody–oligonucleotide conjugates (AOCs). Nucleic Acids Res 2023; 51 :5901–10. https:// doi.org/ 10.1093/ nar/ gkad415
4. Couch JA, Yu YJ, Zhang Y et al. Addressing safety liabilities of TfR bispecific antibodies that cross the blood–brain barrier. Sci Transl Med 2013; 5 :183ra157. https:// doi.org/ 10.1126/ scitranslmed.3005338
5. Pardridge WM, Boado RJ, Patrick DJ et al. Blood–brain barrier transport, plasma pharmacokinetics, and neuropathology following chronic treatment of the Rhesus monkey with a brain penetrating humanized monoclonal antibody against the human transferrin receptor. Mol Pharm 2018; 15 :5207–16. https:// doi.org/ 10.1021/ acs.molpharmaceut.8b00730
6. Hurwitz J, Haggstrom LR, Lim E. Antibody–drug conjugates: ushering in a new era of cancer therapy. Pharmaceutics 2023; 15 :2017. https:// doi.org/ 10.3390/ pharmaceutics15082017
7. Lieser RM, Yur D, Sullivan MO et al. Site-specific bioconjugation approaches for enhanced delivery of protein therapeutics and protein drug carriers. Bioconjug Chem 2020; 31 :2272–82. https:// doi.org/ 10.1021/ acs.bioconjchem.0c00456
8. Mullard A. Antibody–oligonucleotide conjugates enter the clinic. Nat Rev Drug Discov 2022; 21 :6–8. https:// doi.org/ 10.1038/ d41573- 021- 00213- 5
9. Rioja Inma. Bicyclic peptides (Bicycles) as novel multipurpose delivery systems. The BNA 2023 International Festival of Neuroscience. https://www.bicycletherapeutics.com/wp-content/uploads/2023/05/Bicyclic_peptides_as_novel_multipurpose_delivery_systems.pdf

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Date: June 4, 2026
Time: 11am-12pm EDT / 5-6pm CEST

Title: Chance, Choice, and Conviction: A Career in Oligonucleotide Therapeutics

Description:

An insight into how a combination of (taking) chance, role models, mentors, becoming better at making informed decisions, and learning to trust your gut feeling propelled a career in Nucleic Acid Therapeutics. Lean forward!

Speaker: