Nano-Rare, Mega Impact: A Conversation with Stanley T. Crooke, Founder, CEO and Chairman of the Board, n-Lorem Foundation

On this Rare Disease Day, we are delighted to shine a spotlight on the remarkable journey of Dr. Stanley T. Crooke. Occasionally missing seeing patients one-on-one as a dedicated physician, Dr. Crooke went on to found Ionis Pharmaceuticals 35 years ago, where he and his team pioneered antisense technology and transformed drug development in areas of neurology, cardiology, rare diseases, and other specialty areas. Today, with n‑Lorem, Dr. Crooke has turned his focus to the nano‑rare—those patients who are often overlooked by traditional healthcare models. His mission at n‑Lorem is simple yet profound: to deliver personalized RNA‑targeted therapies to patients with nano‑rare diseases, ensuring that even the rarest conditions are met with innovative, life-changing treatments. On this day of reflection and awareness, Dr. Crooke shared his relentless pursuit of a future where no patient is left behind.

Stanley, Greetings! n‑Lorem is pioneering individualized antisense oligonucleotides (ASOs) medicines for nano‑rare diseases. What unique advantages do they offer compared to other modalities?

Stanley T. Crooke: Thanks for having me. The science of n‑Lorem lies in the evolution of RNA technology and my work at Ionis, where we thoroughly validated ASOs. Within a chemical class of ASO, all ASOs behave similarly. This consistency lets us determine optimal dosing, administration routes, and safety profiles based on prior experience.

Many of our patients require highly selective ASOs that target only the mutant RNA and the resulting abnormal protein. Their high selectivity comes from leveraging genetic information directly to target disease-causing mutations, making them versatile, rapid, and cost-effective compared to other drug discovery platforms. No other technology can match that capability. At n-Lorem, we benefit from 35 years of leadership in creating, advancing and validating the technology and have industrialized the process to better assure optimal outcomes for our patients. We have built a highly efficient and experienced ASO discovery and development team capable of meeting the growing demand from the nano-rare community. Our lab is also working on developing new mechanisms to further expand the reach of our approach, broadening the therapeutic possibilities for these patients.

These advantages are recognized by the FDA, which has issued guidance specifically for well-understood antisense agents. In many ways, this is the realization of the vision I had when founding Ionis 35 years ago. Science is a source of miracles, and science creates miracles over time. The journey—from Watson-Crick’s discovery of DNA structure, through the genomics revolution, to the advancement of antisense technology—has culminated in n‑Lorem, allowing us to address the unmet needs of patients who are otherwise left behind.

Could you share the origins of n‑Lorem and explain how its vision has evolved under the nonprofit model?

Stanley T. Crooke: At Ionis, we successfully created medicines for both rare and more common diseases. However, in 2018, I met with parents of patients suffering from extremely rare diseases—so rare that Ionis couldn't justify pursuing them. But in that conversation, I realized our technology could rapidly generate tailored antisense oligonucleotides (ASOs) for these patients.

This realization led me to engage with senior FDA officials and, by January 2020, to establish n‑Lorem. I define 'nano-rare' mutations as those affecting fewer than 30 individuals worldwide. Our mission is straightforward: to address the desperate needs of 'nano‑rare' patients that are impossible for the conventional healthcare system to deal with. Since then, we've processed over 350 applications, initiated more than 100 drug discovery programs, and are now treating above 30 patients. While our scale and funding needs have grown, our core mission remains the same—serving patients and families left behind by conventional drug development.

You're focusing on the rarest of the rare. Roughly how many patients fall into that category?

Stanley T. Crooke: Despite the narrow definition, I estimate there are millions of patients with pathogenic nano-rare mutations. These patients often face a perilous, idiosyncratic diagnostic journey, and there’s no commercial solution today because developing a drug for fewer than 30 patients would require costs that make traditional models unfeasible. In essence, while each mutation is extraordinarily rare, the cumulative number of patients affected is substantial, underscoring the urgent need for novel, patient-centric approaches.

Do you face unique challenges when working with a single patient comparing with large populations while at Ionis?

Stanley T. Crooke: It’s as different as night and day. Shifting from treating large patient populations to focusing on one patient at a time requires a complete change in mindset—evaluating the risk-benefit profile for an individual rather than a group.

After 30 years of scaling up production, we had to downscale significantly. There are very few facilities equipped to manufacture the minute quantities of ASO needed, and formulating them into vials is an additional challenge. Moreover, we need to collaborate closely with vendors and the FDA to establish regulatory pathways in order to deliver these treatments in a timely manner—before patients succumb to their diseases.

Despite the challenges you mentioned above, what excites you at n-Lorem?

Stanley T. Crooke: To date, we've administered over 100 doses, and among the evaluable patients, eight out of nine have experienced profound clinical benefits. This high success rate is a direct reflection of our genetic approach to treat genetically caused diseases.

The benefits we're observing are significant. With our central nervous system therapies, patients have experienced dramatic reductions in seizures, improved mobility, enhanced cognitive function, and accelerated developmental gains. In other areas, such as renal and ocular conditions, we've stabilized kidney function—thereby delaying or even avoiding the need for a transplant—and preserved vision.

Our longest patient has been treated for more than two years. Two years ago, she was wheelchair-bound, nonverbal, and suffering from hundreds of seizures a day. Today, she walks, talks, thinks, and enjoys life. Her seizures and movement disorders are controlled. All of us at n-Lorem feel very much that we're privileged to be a part of this.

With Rare Disease Day falling this month, what do you want to raise awareness about?

Stanley T. Crooke: Today, there’s no established pathway for approving nano‑rare ASOs—we treat these patients under an IND for life. We must reinvent our clinical trial designs and regulatory pathways to better accommodate these ultra‑rare patient populations. Current healthcare systems are built for large populations and are often ill-equipped to handle the unique challenges of the ultra‑rare.

My call to action is straightforward. First, we must incorporate genomic sequencing into newborn screening. Only then can we accurately determine how many rare diseases and patients exist, so that we can identify affected patients early. The evidence is clear: the earlier we treat, the better the outcomes. Early diagnosis and treatment not only save lives but also reduce long‑term healthcare costs and help families regain stability.

Second, we need to rethink our economic models. Traditional reimbursement methods simply cannot sustain treatments that could cost tens of millions per patient. We must explore new models—whether venture philanthropy, cost‑plus pricing, or other innovative approaches—to create an affordable standard of care.

Last but not least, we need to build strong communities for these isolated patients and their families. When individuals come together, they can collectively drive change. We need advances across multiple fronts—diagnostic, clinical, regulatory, and technological—to create a comprehensive infrastructure that truly serves those affected by these devastating diseases.

Thanks, Stanley. Those are really important points—early diagnosis, new economic models, and stronger patient communities all need to come together if we want real change. At WuXi AppTec, we care deeply about making better medicines faster to patients, and it’s clear there’s still a lot of work to do. Really appreciate your insights and the work you’re leading in this space.

Stanley T. Crooke: Thank you for having me.