Throughout the millennia, anyone who had anything beyond a simple illness could only do their best to ease the pain and petition whatever deities their culture believed in. Then, in the past few centuries, medicine and science have advanced to the point that many illnesses and diseases can be successfully treated. Unfortunately, rare diseases have not been given the same attention as common diseases until the past few decades when people finally realized that even if each rare disease only represents a patient population of a few thousand, hundreds, or even a few dozen, all together that still represents an enormous number of people (more than 300 million) needlessly suffering when we now have the tools to begin finding treatments.

Now we have the technology to not only diagnose and treat many rare diseases, but a few shining examples have proven that N of 1 diseases can be diagnosed, medicines designed and manufactured,  and the patients treated with measurable positive results.

Yet, there is still work to be done to make this kind of personalized medicine safe for a wide range of people. Some have received N of 1 treatments with no ill effects, and others have lost their lives. Still others experience clear improvements to their health and quality of life, while also experiencing life-threatening side effects. Thus, we are presented with a challenge. What steps can be taken to make these treatments as safe as possible for the greatest number of patients in the shortest time frame? There is great urgency because no parent should have to decide whether to give their child a medicine to improve their quality of life, knowing that it is likely to cause complications that will shorten their life.

ASOs – from treating rare diseases to the first N of 1 drug

Spinraza (nusinersen) is an antisense oligonucleotide that was developed to treat spinal muscular atrophy, a rare neuromuscular disorder. Little did those involved know that its development and FDA approval would pave the way for the very first personalized N-of-1 treatment for a single person with a unique genetic disease.

The first antisense oligonucleotide used in an N-of-1 treatment was developed for Mila Makovec, who was 6 years old at the time. Dr. Timothy Yu at Boston Children’s Hospital identified a splicing defect in one of her genes and theorized that an ASO similar to nusinersen could be used to correct the splicing defect. Using the same chemical backbone and route of administration as nusinersen, within one year, Dr. Yu and a large team of colleagues developed an effective ASO, tested and confirmed that it was safe in rats, achieved FDA approval for an N-of-1 trial, and began treating Mila with the new drug, Milasen, with carefully escalated doses over a 6 month period until the target dose was achieved (1, 2, 3). In an interesting podcast, Dr. Timothy Yu was interviewed and detailed many of the steps he and his team took in creating Milasen, running safety studies, getting sufficient evidence, quality control data, safety data from animals, communicating with the FDA, and more. When asked about the timing, he explained, “For this to be worth it, we would have to move very fast. This is a condition that we knew would be terminal in just a few short years… She would lose quality of life on a monthly basis.”

Their work did help Mila. Milasen significantly improved the severity and frequency of seizures that she experienced while slowing the progression of symptoms (1). With Milasen, Dr. Yu and his team proved that not only are N of 1 drugs possible to create but that it can be done with astounding swiftness. Since Milasen, other N-of-1 drugs have been developed, often with great success in treating the disease, reducing symptoms, and improving quality of life for the patient.

Valeriasen

In 2018, a sweet baby girl named Valeria was born with a pathogenic KCNT1 variant that caused her to have dozens of seizures a day. KCNT1 is a gene that encodes a ligand-gated potassium channel, and mutations in the gene cause many epilepsy phenotypes, many of which begin in infancy. Pathogenic variants most commonly cause intractable seizures, with those afflicted experiencing 40-100 seizures a day. At least 200 cases have been identified, with one prevalence model predicting up to 3000 cases may exist worldwide.

KCNT1-related epilepsy often responds poorly to antiepileptic drugs, and there is currently no effective therapy (4). This was confirmed in an international study of twenty-seven children with pathogenic KCNT1 variants that found that although several anti-epileptic drugs, cannabidiol, and diet therapies were tried and provided reasonable response with some seizure reduction, no single agent delivered a consistent response (5). This leaves patients’ families and their medical team to use a trial-and-error approach to treatment, hoping they happen to find a treatment, or combination of treatments, that provides relief.

Rather than rely solely on anti-epileptic medicines that merely treat the symptoms, Valeria’s parents, Mario and Alexandra Schenkel, wanted to search for a cure. Much effort into researching the condition and potential treatments led Valeria’s parents to reach out to Dr. Yu to help their daughter, and they learned that an antisense oligonucleotide could possibly be a solution. As the cost of developing an ASO to treat an orphan disease is not covered by insurance, they had to raise the money themselves, a common burden for parents of children with rare genetic diseases.

Valeria’s entire genome was examined, the effect of her specific mutation was discovered, and many steps were taken to design and test an ASO and receive FDA approval to administer the drug called Valeriasen. (See an excellent breakdown of the timeline of events at the Valeria Association.) Finally, in September of 2020, treatment began with very small doses administered, increasing incrementally until the target dose is reached. Incredibly, the daily seizures she endured became less frequent within weeks of receiving the ASO.

Sadly, there was a side effect, hydrocephalus, that caused fluid to build up in her brain, and Valeria died a year later. Despite their loss, Valeria’s parents are maintaining the Valeria Association in Switzerland and the Valeria Foundation in the USA to support the treatment of ultra-rare diseases. Her father said, “Neurologists shouldn’t be scared of being bold and trying these kinds of drugs and helping patients with rare diseases.”

“She was such a fighter,” her mother shared. “She was the one who paved the way for KCNT1 research and all the children who will hopefully get the chance for a better quality of life.”

One other patient, Lucy Greenblot, also received Valeriasen. Lucy began taking the drug at age 2.5, after which she only experienced a few seizures a day, and some days was seizure free. Unfortunately, she also developed hydrocephalus and discontinued the treatment within two months. Since then, she has endured as many as 15 seizures a day. Now, her parents have to decide which will cause less suffering for their daughter.

Lucy’s father, Seth Greenblott, explained, “We know our time with her is limited, and this may be our best hope to improve the quality and length of her life. But we also know we could shorten her life and make it harder. I don’t know how anyone makes that decision.”

Further complicating the situation is the fact that hydrocephalus is not uncommon in people with neurological diseases, which makes it difficult to definitively determine whether the drug or the underlying disease is the cause. However, three people who received an ASO to treat Huntington’s disease in a Roche clinical trial developed hydrocephalus, as have some patients on nusinersen, an ASO drug approved to treat spinal muscular atrophy.

Dr. Yu and his team are investigating what caused hydrocephalus in Valeria and Lucy, and if adjusting the dose could minimize the risk.

CRISPR N-of-1 Trial

ASOs are not the only avenue for N-of-1 treatments. CRISPR drugs are being developed that are proving to be safe and effective. At the same time, there are some risks involved, as there are in developing any new therapy.

Cure Rare Disease is a nonprofit founded by Rich Horgan, whose 27-year-old brother, Terry, was diagnosed with Duchenne Muscular Dystrophy. Cure Rare Disease works with a multidisciplinary, multi-institutional group of scientists, including those at Yale Medical School and UMass Chan Medical School. An N-of-1 CRISPR therapy was developed to treat Terry and received FDA approval to proceed with an N-of-1 trial.

While not much is known at this point, news of Terry’s death was released a little over a month after the trial was supposed to begin.

Cure Rare Disease released a statement in which they explained that multiple teams are studying details of the trial that is “critical to gaining a clear understanding of the outcome of the CRD-TMH-001 trial and to shedding additional light on the challenges of gene therapy broadly.” They intend to share the findings “to further the understanding of AAV-based gene therapies and applications among the larger communities for the treatment of other rare diseases.”

Arthur Caplan, a medical ethicist thinks this death “may make us think whether we really do like studies that are just on one person, and do we want to say: ‘No, ethically, you’ve got to at least have a trial where you line up 5, 10, 20 people (and) you learn from the data.’” If we take that approach, though, people with individual mutations will never be able to receive, or even test, a treatment.

The Future of N-of-1 Trials

Perhaps a more balanced view comes from Fyodor Urnov, a CRISPR expert at the Innovative Genomics Institute at the University of California, Berkeley, who stated that “History teaches us that in the case of such fatalities – which have been rare – that a deep dive into what happened was critical for the field to move forward.”

Dr. Timothy Yu says much the same thing. “We have to learn as much as we can from each and every one, because they’re just so incredibly valuable in every sense.”

Liza-Marie Johnson, a pediatric oncologist and bioethicist at St. Jude Children’s Research Hospital, brings up an important consideration. “How do we share data and monitor so that we can learn from events and make this safer and potentially benefit future patients?”

Undoubtedly, ongoing assessments will be important in this new way of developing drugs for these ultra-rare disorders, as will a sharing of discoveries. David Williams, MD, chief scientific officer at Boston Children’s, explained that in launching N-of-1 trials they “have set up robust processes to ensure scientific rigor and patient safety, and to consider ethical questions,” all of which will also be vital to a future in which N-of-1 treatments are common.

Many patients with ultra-rare diseases are children and infants, which brings an additional layer of ethical challenges in drug development.

There are numerous foundations that have been created to find innovative cures for those who have diseases. Often the families of those diagnosed are the driving forces behind the creation of foundations, such as the Valeria Association, the KCNT1 Epilepsy Foundation, Cure Rare Disease, and Mila’s Miracle Foundation.

The N=1 Collaborative was recently launched as the first international hub for individualized medicines for rare diseases, with hundreds of participants who are dedicated to guiding this rapidly developing new branch of medicine. The organizing committee is comprised of scientific leaders from around the world, including Dr. Tim Yu, the designer of Milasen, and Julia Vitarello, Mila’s mother.

And these nonprofits all have much to say on the matter of ongoing assessments, sharing of discoveries, and the future of N-of-1 treatments…

Cure Rare Disease has made its position clear with its intent to share findings of the CRD-TMH-001 trial “to further the understanding of AAV-based gene therapies and applications among the larger communities for the treatment of other rare diseases.”

The Valeria Association explains from their experience, “It turns out that it takes a lot of time to find all the people who have the necessary know-how and bring them together. Parents of children with orphan diseases know that time is the most precious commodity. The process of bringing together the right people, universities or institutions until the right medicine is available must be faster and easier.”

“The more experience and data are gathered with this new technology, the easier and faster these processes will be in the future. The design and production of an oligo does not have to be “reinvented” every time. If the ASO approach is the right one, the processes are the same, regardless of the gene mutation. The standardization of various steps, such as the approval procedure by approval authorities and associated test procedures, should result in shorter and more cost-effective processes.”

Those involved in the N=1 Collaborative wholeheartedly believe in sharing data and working together to bring individualized treatments to rare disease patients as safely and quickly as possible. They have formed workgroups focused on critical steps in the development of an individualized drug, with an emphasis on data sharing and establishing best practices, and have created workshop resources to further that goal.

Their vision is to pioneer drug development for individual patients through fostering collaboration which includes establishing community expectations, best practices, safety and quality standards, and ensuring clinical trial readiness. Fulfillment of their vision also includes nurturing the field by picking good cases, minimizing duplication of preclinical and clinical effort through sharing of data and learnings (case conferences, safety databases, cross referencing INDs), and harmonizing global efforts.

With so many different groups working to provide treatments for ultra and nano-rare diseases, hopefully, a century from now, humanity will look back on this decade as a time in which incredible progress was made with unprecedented levels of international collaboration and sharing of discoveries as ongoing innovation and long-term assessments reveal knowledge that can save millions of lives.

References:

1. Kim, J., Hu, C., Moufawad El Achkar, C., Black, L. E., Douville, J., Larson, A., Pendergast, M. K., Goldkind, S. F., Lee, E. A., Kuniholm, A., Soucy, A., Vaze, J., Belur, N. R., Fredriksen, K., Stojkovska, I., Tsytsykova, A., Armant, M., DiDonato, R. L., Choi, J., Cornelissen, L., … Yu, T. W. (2019). Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease. The New England journal of medicine, 381(17), 1644–1652. https://doi.org/10.1056/NEJMoa1813279
2. Mullard A. N-of-1 drugs push biopharma frontiers. Nat Rev Drug Discov. 2020 Mar;19(3):151-153. doi:10.1038/d41573-020-00027-x. PMID: 32127676.
3. Cross, Ryan. “Milasen: The Drug That Went from Idea to Injection in 10 Months.” C&EN, Chemical & Engineering News, 16 Oct. 2019, cen.acs.org/business/Milasen-drug-idea-injection-10/97/i42.
4. Burbano LE, Li M, Jancovski N, Jafar-Nejad P, Richards K, Sedo A, Soriano A, Rollo B, Jia L, Gazina EV, Piltz S, Adikusuma F, Thomas PQ, Kopsidas H, Rigo F, Reid CA, Maljevic S, Petrou S. Antisense oligonucleotide therapy for KCNT1 encephalopathy. JCI Insight. 2022 Sep 29:e146090. doi: 10.1172/jci.insight.146090. Epub ahead of print. PMID: 36173683.
5. Borlot F, Abushama A, Morrison-Levy N, Jain P, Puthenveettil Vinayan K, Abukhalid M, Aldhalaan HM, Almuzaini HS, Gulati S, Hershkovitz T, Konanki R, Lingappa L, Luat AF, Shafi S, Tabarki B, Thomas M, Yoganathan S, Alfadhel M, Arya R, Donner EJ, Ehaideb SN, Gowda VK, Jain V, Madaan P, Myers KA, Otsubo H, Panda P, Sahu JK, Sampaio LPB, Sharma S, Simard-Tremblay E, Zak M, Whitney R. KCNT1-related epilepsy: An international multicenter cohort of 27 pediatric cases. Epilepsia. 2020 Apr;61(4):679-692. doi: 10.1111/epi.16480. Epub 2020 Mar 13. PMID: 32167590.

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