OTS Member Highlight – Dr. Annemieke Aartsma-Rus
Growing up the oldest of four children in Leiden, Netherlands, Dr. Annemieke Aartsma-Rus became fascinated with medical research and genetics as a teenager.
While her father’s work as a physician made her realize she didn’t want to be a doctor, it did teach her that there were numerous diseases with no treatments. In high school, Aartsma-Rus was introduced to scientific research through her subscription to a Dutch academic magazine, which ultimately influenced her to study biomedical science.
Now a prominent figure in the field of medical research, particularly for her pioneering work on oligonucleotide therapies for Duchenne Muscular Dystrophy (DMD), Aartsma-Rus’s career reflects not only her dedication to rigorous scientific exploration but also her deep compassion for the patient community.
A serendipitous match: entering the field of oligonucleotides and Duchenne Muscular Dystrophy
After completing her MSc internship at the Department of Human Genetics, Aartsma-Rus was offered a PhD project on Duchenne Muscular Dystrophy (DMD) — a serious and fatal genetic disease that causes progressive muscle weakness and breakdown, eventually leading to early death in boys and men worldwide.
“As I liked genetics and the project sounded interesting, and I liked the open and collaborative environment of the Department, I accepted the position,” she said.
However, the project turned out to be based on an artifact and went nowhere. Fortunately, Aartsma-Rus’s supervisor offered her a side project: designing and testing antisense oligonucleotides for exon skipping in DMD. Patients with DMD do not have the dystrophin protein because its gene code is unreadable. Exon skipping aims to slow the disease progression by making the code readable, thus producing partially effective dystrophin.
Since then, her work and contributions in the oligonucleotide field, specifically in treatments for DMD, have been significant. Studies Aartsma-Rus is proud of are obtaining proof-of-concept for dystrophin restoration in patient-derived cell cultures, demonstrating that even very small levels of dystrophin can improve pathology in mice and generating a humanized mouse model for DMD.
“After screening thousands of clones, we finally managed to make a mouse with the human dystrophin gene with a mutation,” she explained. “This model allows testing human-specific ASOs in a mouse background, for easier translation from mouse to trial.”
From helping to pioneer the antisense-mediated exon skipping approach for DMD to providing guidelines on the characteristics of effective and non-effective exon skipping ASOs and much more, Aartsma-Rus has made a meaningful mark in the field.
“While my entrance to the fields of Duchenne and Oligonucleotides was serendipitous, I did not leave once entering. Both fields are characterized by a collaborative and positive attitude that I really enjoy.”
Her love of the oligonucleotide field is not just about the science but the community of researchers that value rigorous science. When she was a young scientist, Aartsma-Rus went to the first two OTS meetings in New York where, in addition to great educational value, community, and the accessibility of the leaders in the field, she says it was the first time people actively engaged with her during the poster session.
“This made me realize this was a field I wanted to be part of, and when possible, I wanted to give back to the society.”
Learning from and overcoming setbacks
While Aartsma-Rus knew she wanted to work in the oligonucleotide field, she started when the appeal and general scientific hype about the science was in decline. Additionally, her focus was on splice modulation — a less known approach — meaning she constantly struggled against reviewers who were not necessarily knowledgeable about the area or didn’t believe the data or its ability to be translated into clinical application.
Aartsma-Rus and the international groups working on exon skipping and splice modulation overcame this by doing rigorous science, demonstrating promising results, and corroborating each other’s findings independently in different model systems.
However, this was not the only challenge she would have to overcome. In 2013, drisapersen — a drug she was working on for the treatment of DMD in collaboration with Prosensa Therapeutics and GSK — failed to show significant results during its phase 3 clinical trial. The previous clinical development had gone exceptionally well and demonstrated promising results, so the failure and ultimate termination of the trial came as a shock.
“This was a big setback to the patient community,” Aartsma-Rus explains. “As a field, we have overcome this by analyzing what went wrong where. Personally, I have been involved in sharing this story with the scientific field and the patient community so that future research and developments can be better.”
She’s also started educating and training patient representatives, researchers, and healthcare professionals about therapeutic development.
“When clinical development fails, very often, this is not only the fault of the compound. There are many other factors that are involved, and it is important that people working in the field are aware of these so they can anticipate them.”
Thanks to the work of Aartsma-Rus and others, there is now an exon-skipping therapy approved for treating DMD in the United States and Japan.
In addition to her work as a professor of Translational Genetics at the Leiden University Medical Center, she’s also currently working with the N=1 Collaborative, which consists of doctors, researchers, patients, and companies committed to growing the area of individualized medicines. Underpinning her motto that it is important to learn from mistakes, she says she’s applying the lessons she learned from drisapersen to the challenges of creating individualized ASO treatments.
While there are obstacles to overcome, Aartsma-Rus says she enjoys working with a group of such dedicated people in setting up processes and procedures and applying her many learnings from the Duchenne and drisapersen development to help facilitate this work. She considers N=1 ASOs to be a significant development in the field; while each ASO may only apply to one person, combined, the many ASOs will greatly inform the field. Notably, she says there are now more single N=1 ASOs to treat patients than there are approved ASOs to treat larger patient populations.
Science should be fun: collaborations and mentorships
As with ASOs, Aartsma-Rus says there are some collaborations that work and some that don’t. She personally likes collaborating with people who have complementary expertise.
“I’ve learned to stop the collaborations that are difficult and to focus on those that do work,” she said. “Science should be fun, and collaborations should be nice and give energy.”
Beyond working with other scientists, she also intentionally tries to collaborate with and listen to Duchenne patients who have irreversibly lost muscle tissue and function to understand what they expect from a treatment. Notably, patients are especially concerned about not losing further function, an important aspect that motivated Aartsma-Rus to keenly focus on slowing the disease progression and ensuring clinical trials don’t overly burden the patients.
“What this has taught me is to focus on what I have rather than what I do not have anymore. This is a very good life lesson that I try to apply in daily life.”
As a mentor to her students and postdocs, Aartsma-Rus tries not to be oppressive and encourages her mentees to independently give direction to their research under her guidance.
“Very often, mentorship means listening to people and with some pertinent questions allow them to find their own solutions.”
Her own mentors have informed her thoughtful approach to guiding her mentees. One formal mentor was regimented, assuming that what worked for them would work for her — which taught Aartsma-Rus that this was not the type of mentor she wanted to be. However, other informal mentors, particularly Gert-Jan van Ommen and Brett Monia, were meaningful guides in her work and career.
Van Ommen was the head of her department, and when Aartsma-Rus became a junior group leader three years after receiving her PhD, she says he was the perfect mentor, giving her the freedom to decide and make her own mistakes but imparting advice when she asked.
In 2017, when she was elected president of the Oligonucleotide Therapeutics Society (OTS) — which she served for three years — the society was in a transition stage in increasing its size and membership. Aartsma-Rus says Monia was always willing to listen, respond to her emails, and guide her in the right direction.
As for young scientists interested in pursuing a career in the oligonucleotide field, Aartsma-Rus says it’s the perfect time to enter. Now that the approach itself has been proven, there’s lots of opportunity to shape the field, which she notes is still young enough that many people who established it are still around.
“Also, due to the OTS, the field is very science-driven, so whether you work at a company or in academia, there will be a strong focus on science and research.”
Delivery, education, and awareness: developments and obstacles to overcome in the field
While Aartsma-Rus considers the development of tissue delivery modalities to be a breakthrough in the field, with GalNAc solving liver delivery and also expanding research to other tissues, there are still delivery obstacles to overcome.
“As is often said during OTS meetings: our biggest challenges are delivery, delivery and delivery,” she says, adding that for each tissue that is ‘unlocked,’ there are new targets for ASOs.
Infrastructure, understanding, and awareness are also aspects she’d like to see improved, noting that there’s often little expertise in clinical trial design for rare diseases where ASOs are a potential therapy.
“As showcased with the drisapersen story, this is very challenging,” she says, explaining that when a trial design is suboptimal due to limited or no data on natural history and/or outcome measures, it’s challenging to show if a treatment works.
“When a treatment is very effective, all of this will matter less. However, for rare diseases, very often, we expect a slower progression. Then having good outcome measures and clinical trial infrastructure in place is crucial.”
Educating the public and health care professionals about what oligonucleotides are, how they work and what role they can play is also essential, Aartsma-Rus says. Noting that for Duchenne Muscular Dystrophy, there have been sad examples of neurologists prescribing eteplirsen — a drug that skips exon 51 — for patients with an exon 51 deletion, failing to understand the mechanism of action of the drug.
“This leads to devastation with the Duchenne families: first the blow of the diagnosis, then the hope that for their son there is a treatment, to then be told that actually there is not.”
Artificial intelligence and machine learning are also developments that Aartsma-Rus believes will help make successful and safe ASOs. She explained that the increase of scale from N=1 ASO efforts will provide data for the machine learning on a few patients with many ASOs compared to approved ASOs, which supply data on many patients with a few ASOs.
“We need to feed the systems data of things that work and are safe, but also ASOs that did not work or were not safe. That will give much more robust models than only focusing on what works.”
Finding a balance: books, origami, and beats
With over 250 peer-reviewed papers, 11 book chapters, and 15 patents, Aartsma-Rus is busy. However, she acknowledges the importance of setting work boundaries.
“Once people are used to you always working, they will expect it.”
Some of these boundaries include staying offline while on vacation and not feeling guilty when she doesn’t work on the weekends or evenings. Additionally, her 2014 New Year’s resolution, which she still maintains, was not solving other people’s lack of planning.
“So if someone sends me a project or something else on Friday just before the weekend and the deadline is Monday morning, that is too bad for them,” she says. “They will not dictate that I work on the weekend because they were too slow. Sometimes this causes some surprises or frustrations, but overall, people respect this, and they learn.”
As for what she enjoys doing outside of scientific work, Aartsma-Rus reads a lot of books, enjoys making origami animals — which she says helps her stay focused during meetings and make great gifts — and playing Beat Saber (a VR rhythm game) on her Oculus Quest.
“It is a good way to stay fit, and also, you can bring your gym with you when you go to conferences.”
Accomplishments and Accolades
Since 2016, Aartsma-Rus has been considered the most influential researcher in the field of Duchenne Muscular Dystrophy. Her many accolades include the Duchenne Award from Duchenne Parent Project the Netherlands, being admitted to the Jonge Akademie (the junior section of the Dutch Royal Academy of Sciences, consisting of the 50 most prominent Dutch scientists below age 45), serving as an OTS President, a member for the scientific committee of the International Rare Disease Research Consortium (IRDiRC), a board member for the Leiden Network for Personalized Therapeutics, and the scientific advisory board for numerous patient organizations.
As a teenager, Annemieke Aartsma-Rus knew from her father’s work and her academic reading that the number of diseases that did not have a cure outweighed those that did. Even now, 95% of rare diseases have no treatment. But Aartsma-Rus’s pioneering work and patient-focused perspective have changed the treatment options for the rare Duchenne Muscular Dystrophy.
“It’s crucial for researchers to listen to the patient voice because they are making the therapies for the patients,” she says.
To stay up to date with Dr. Annemieke Aartsma-Rus’s research and contributions, she can be followed on Bluesky, her Exon skipping website, and the Dutch Center for RNA Therapeutics.
Key Highlights of Dr. Aartsma-Rus’s work:
The state-of-the-art of N-of-1 therapies and the IRDiRC N-of-1 development roadmap
Therapeutic antisense-induced exon skipping in cultured muscle cells from six different DMD patients
Systemic administration of PRO051 in Duchenne’s muscular dystrophy
