Holly Kordasiewicz was a curious, chatty child with a penchant for asking questions. At dinner, conversations were often about the fascinating things her mom, a registered nurse, learned at work, sparking Kordasiewicz’s interest in medicine and biology. As her grandparents aged, and she witnessed neurodegenerative diseases gradually and relentlessly chip away at those she loved, her desire to study the brain grew.

“One of my grandfathers had Parkinson’s disease, and the other had Alzheimer’s, and one of my grandmothers had dementia,” Kordasiewicz shared. “So, we have a lot of neurodegenerative disease in my family, and I saw firsthand what that does…many [neurodegenerative diseases] can take away what makes someone who they are, and it feels particularly tragic.”

From an early age, Kordasiewicz was encouraged to explore and find an answer to her questions. In undergrad, she studied psychology and was invited by a professor to work in a lab. Additionally, Kordasiewicz volunteered in a lab at a larger university while finishing her undergraduate work, solidifying her desire to do a PhD in Neuroscience, which she later received from the University of Minnesota in 2006.

While completing her graduate work, she was constantly frustrated that researchers could understand a disease but have no clear path to treatment. So, as she was applying for postdoctoral positions, she was encouraged to apply to Don Cleveland’s laboratory at the University of California San Diego.

At the time, Cleveland was preparing to publish the preclinical work supporting the first superoxide dismutase (SOD1) antisense oligonucleotide (ASO) for treating SOD1 Amyotrophic Lateral Sclerosis (ALS) with Ionis. During her interview, he explained how delivering ASOs to the central nervous system (CNS) worked, showed her the data, and she was hooked.

“This was the solution neurology needed. It was so simple, targeting the RNA of the mutant gene. It really felt like something that could work,” she said.

Kordasiewicz worked for eight years at Cleveland’s lab on ASOs that lower the Huntington RNAs (1) in mouse models, which she says worked shockingly well. During this time, she worked closely with the team at Ionis Pharmaceuticals, where she is now the Senior Vice President of Neurology.

“They [the team at Ionis] were all just really wonderful, very science and data-driven where everyone’s goal was to help someone and not just to help them a little, but to really try to change people’s lives – so a whole group of people with that as their focus, I wanted to be a part of it.”

Research on neurological diseases and meaningfully helping patients

Currently, Kordasiewicz heads a team at Ionis focused on discovering and optimizing ASO therapeutics for neurological diseases and conditions like ALS, Alzheimer’s disease (AD), Alexander disease, Angelman syndrome, and Prion disease. In 2019, she was awarded the Young Investigator Award from OTS. Her research has focused on understanding delivery of ASO to the brain and how best to design and optimize delivery of these large macromolecules to the CNS.

“Understanding these basic principles has been key to developing therapies and continuing to advance the oligonucleotide therapeutics field.”

Kordasiewicz has significantly contributed to research on validating targets for treating neurological diseases in preclinical model systems and identifying molecules suitable to advance to clinical testing for neurological diseases. She says anything that meaningfully helps a patient is work she’s proud of and, “the best feeling in the world.” QALSODY® (tofersen) — a treatment for individuals living with SOD1-ALS, an ultra-rare genetic form of ALS — is a project Kordasiewicz is proud to have worked on alongside researchers at Biogen. The data from the first-in-human SOD1-ALS trial was shared by Biogen during a collaborative session, and she says she’ll never forget how silent the room became as the results were  revealed that the trial patients — who carried the SOD1 mutation that causes one of the most devastating and progressive forms of ALS — hadn’t progressed since receiving the drug.

“This is a relentless disease, and in a few months of that study, they should have gotten worse, and they didn’t. And those were real people who got better because of what we do, and I just can’t even begin to describe that feeling that we might actually be helping someone.”

The MAPT program (2), which developed an ASO targeting MAPT, the gene that encodes the protein Tau (3), is another project Kordasiewicz is proud of. Tau tangles are a hallmark of Alzheimer’s disease and have proven challenging to address with traditional protein targeting modalities. However, she explains that ASOs offered a novel solution by preventing the production of tau at the RNA level. Preclinical models showed that this approach could reverse tau pathology, and for the Phase 1b clinical study, she strongly advocated for incorporating tau positron emission tomography (PET) imaging to evaluate whether the findings in animal models could translate to human patients.

“I had a lot of fun debates with folks who had been in the AD field for years and said this wasn’t possible,” she says. However, the results showed the tau pathology was reversed in AD patient brains after ASO treatment.

“This was incredible. The Phase 2 trial for this ASO, which is led by Biogen, is reading out next year and in this study, we are asking the question, ‘Can lowering tau and reversing tau pathology have an impact on disease?’”

Overcoming research hurdles: behind each gene is a person

As these achievements shape the field and potential patient therapies, Kordasiewicz notes that most research doesn’t work out, and investigating why some oligonucleotides fail acute safety studies in the CNS is an area she’s interested in.

“We’ve found there are two unique mechanisms that are often lumped together, which has made untangling the mechanisms of the two phenomena challenging. We recently posted two manuscripts on BioRxiV explaining these unique mechanisms” (4, 5).

Kordasiewicz explains there’s always a challenge when advancing a platform into a new space. The initial hurdle for ASOs in the CNS was distribution and delivery to large animals, which required understanding cerebral spinal fluid (CSF) dynamics and how best to harness this to achieve broad distribution in the CNS. Then came tolerability issues, and once that was solved, it was trying to advance the platform to make it more convenient for patients, she says. Now, it’s working on delivering oligonucleotides across the blood-brain barrier (BBB).

“It’s always a challenge, and how we overcome them is to not give up and know that patients are waiting for us to get this right,” Kordasiewicz says. “Invest in the fundamentals and take the time to understand the mechanism and underlying biology.”

She also makes a point to celebrate the wins when they happen and to remember that they’re out there. Despite the challenging nature of the work, she says it’s easy to stay motivated by keeping the patient’s perspectives in mind and remembering that behind each gene is a person.

“With these neurodegenerative diseases, they’re going to get worse, and they’re going to get to a point of no return, and their diseases aren’t going to wait for anyone. So, you just do it, and you keep going.”

Game changers in the oligonucleotide field

This mentality of perseverance is what brings significant developments to the field. Kordasiewicz says that for someone in the neurology space, the most transformative advancement in the field was Ionis’ discovery and co-development of SPINRAZA® (nusinersen), which Ionis licensed to Biogen in 2016 for further development and commercialization. SPINRAZA was approved by the FDA later that year as the first-ever treatment for spinal muscular atrophy (SMA), which underscored the potential of oligonucleotides in the CNS from a crazy idea to a powerful therapeutic option.

“This is a drug that’s taken children who were fated to die from an inherited neurodegenerative disease, to meeting normal developmental motor milestones. It highlights the power of an RNA therapeutic and what can happen if you target the underlying disease. It’s a game changer.”

As for future developments in the field that excite her, it’s the ability to deliver oligonucleotides to broader patient populations, which, if current studies in larger populations pan out, will be a milestone for the oligonucleotide field. She adds that Ionis’ additional programs in neurology, cardiology, and other areas of high patient need have great potential to help millions once they play out in clinical trials. Additionally, Kordasiewicz eagerly anticipates new delivery opportunities for the CNS, like BBB and annual IT dosing.

“This will make it more convenient for patients and give them options for their treatment, and I love that.”

The role of artificial intelligence (AI) is also a process she says is positively impacting the field, allowing drugs to be developed more efficiently.

“One of the challenges with drug discovery, particularly molecule identification, is the sheer number of permeations that are possible. This is a great place for AI. Also, general efficiencies in how all of us in science work are already being realized with AI.”

Collaboration and mentorships: follow the data, find your voice, and dream big

Treating untreatable diseases can only be accomplished through collaboration, whether with fellow scientists or patients; Kordasiewicz firmly believes this and loves that Ionis fosters a team environment that pairs scientists and physicians who know the diseases best with researchers who know oligonucleotides. This collaboration extends beyond scientists and institutions, she explains, and as the drugs move into development, Ionis works closely with patient organizations and advocacy groups to ensure that patient and community perspectives are pulled through and represented in the work Ionis does.

“That is really powerful. These are the individuals living with the disease, and we can learn firsthand about the disease, the impact of the disease on families and the needs of the people we are trying to help. Our work isn’t possible without these collaborations.”

Working with other people, both as a mentor and mentee, has been a critical aspect of her career, and she says she’s had the privilege of working with wonderful, unique, and talented mentors, each of whom had a different style and has taught her something new.

Her most recent mentor, Eric Swayze, Executive Vice President of Research at Ionis, taught her about interrogating the science, oligonucleotides, and drug development – both challenging and encouraging her for years. As a mentor herself, Kordasiewicz loves seeing the next generation grow, innovate, and challenge dogma and preconceived notions while fostering new ideas and ways of thinking. When a mentee asks for her thoughts on something, she encourages them first to tell her their thoughts, which she says is a good exercise in refining their rationale and finding their voice, while also allowing her to think about things from a different perspective.

“I learn as much from my mentees as they do from me,” she says. “It’s a rewarding and important part of what we do – growing that next generation of scientists and leaders. It’s lots of fun too.”

For young scientists interested in the oligonucleotide field, Kordasiewicz’s advice is to, “figure out what you love, what you’re good at, and what motivates you.” With so many opportunities in the field, Kordasiewicz says it’s about finding what works best for each person — from inventing new techniques to investigating an unknown problem or developing a new therapy — and she sees part of her role as a mentor to help those on her team find their perfect position.

“All of it needs to happen, and the most successful and fulfilled folks I know are the ones doing what they love and what fits them.”

Growing up, Kordasiewicz’s dad loved to debate, teaching her to think critically and independently and defend her position — a skill which has helped her immensely in her career and which she encourages young scientists to develop, advising them to find their voice and have the courage to share their vision. Kordasiewicz always walks into a discussion with a recommendation and a position, but this doesn’t mean she’s dogmatic and unable to change her opinion based on the data.

“Ask the right questions. Follow the data. Dream big. Push the envelope. That’s just good advice for anyone.”

An incredible support system: balancing work and family

Long ago, Kordasiewicz decided on the type of work-life balance she needed to make herself and her family happy, which includes a family dinner and logging off for a few hours every night before working before bedtime. She loves spending time with her family, traveling, and exploring San Diego with her eight-year-old daughter.

“I have an incredible support system in my husband and family, and they support me in my professional life and their help makes it possible for me to be able to do what I do.”

While her work is guided by science and data, it’s the patients and their families that drive Kordasiewicz and her team. Her work at Ionis holds the possibility of transforming treatment options for a broad range of rare neurological and neurodegenerative disorders, ultimately helping countless individuals and families affected by these relentless conditions. At the end of the day, Kordasiewicz says if she could be remembered for anything, it would be that the work she did made someone’s life better in a meaningful way.

Stay updated with Kordasiewicz’s latest research and contributions through conferences, publications, and by following Ionis on X (Twitter), LinkedIn and Instagram.

References and Key Publications:

1. Translating Antisense Technology into a Treatment for Huntington’s Disease – PubMed
2. Exploratory Tau Biomarker Results From a Multiple Ascending-Dose Study of BIIB080 in Alzheimer Disease: A Randomized Clinical Trial – PubMed
3. Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial – PubMed
4. Reversable Acute Sedation Response of Phosphorothioate Antisense Oligonucleotides Following Local Delivery to the Central Nervous System – bioRxiv
5. Transient Acute Neuronal Activation Response Caused by High Concentrations of Oligonucleotides in the Cerebral Spinal Fluid – bioRxiv
6. The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration – PubMed
7. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis – PubMed
8. Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints – PubMed
9. Antisense oligonucleotides extend survival of prion-infected mice – PubMed
10. A single-cell map of antisense oligonucleotide activity in the brain – PubMed
11. RNA-targeted therapy corrects neuronal deficits in PACS1 syndrome mice – PubMed