Retirement typically means more time for traveling, hobbies, and relaxation. For Stan Crooke, M.D., Ph.D., it means something very different. Crooke, the founder and executive chairman of Ionis Pharmaceuticals, having served as CEO for more than 30 years, will officially retire this year. Instead of hitting the golf course, he is throwing himself into the foundation he and his wife, Rosanne Crooke, Ph.D., started just over one year ago—the n-lorem foundation. N-lorem’s goal is to provide free, individualized, antisense oligonucleotide (ASO) treatments to patients living with ultra-rare (1 to 30 patients worldwide) diseases for life. The funding for n-lorem comes from the Crookes, IONIS, and Biogen.
ASOs are short, single-stranded oligos that are designed to bind to mRNA. The ASOs can serve as a disease treatment because they are specifically targeted to an mRNA that is producing a disease-causing protein. Prior to starting n-lorem, IONIS helped two investigators design and provide experimental ASOs. Timothy Yu, M.D., Ph.D., at Boston Children’s Hospital for Batten’s Disease and ataxia-telangiectasia (AT); and Neil Shneider, M.D., Ph.D., at Columbia College of Physicians and Surgeons for ALS caused by a FUS mutation.
Crooke tells Clinical OMICs that the first year of n-lorem was “quite successful.” He guessed that they would receive about five applications and that only a fraction oft he applications would be treatable. Crooke thought that it would be hard for people to digest the novelty of an organization that would strive to create a medicine to treat a single patient and provide that medicine free for life—it seems so impossible. In fact, n-lorem received 50 applications in the first year, each with unique mutations, and are proceeding to treat roughly 20 of them.
Part of the success of that first year comes from Crooke’s uncompromising dedication to quality. He worked for years before launching n-lorem to put systems in place that assure both rigorous decision-making and quality ASOs. For example, one of the prime objectives of n-lorem is the evaluation of ASOs’ performance, which they plan to publish in the scientific literature. He adds that this level of scholarship and transparency is vital to n-lorem’s mission.
Crooke, who is quick to note that he works for his patients first and shareholders second, says that he first thought to start n-lorem when he realized that ASOs were capable of treating children with genetic diseases. Once he realized that, he explains, it became a moral question: “If I had the potential to do this, how could I not?” he recalls.
Although he admits that running n-lorem is not something he always envisioned as part of his retirement, he insists that he “can’t not do it, jiminy Christmas!” Thinking about his patients, he says, “I had to.” He adds. “I didn’t have a choice.”
No other choice
Kelley Dalby’s search for a treatment for her son Connor started when he was very young. He started having seizures when he was just eight months old. Connor is 11 today, the middle of Dalby’s three boys.
Connor, Dalby explains, suffered 50 or 100 seizures a day. Available medicines were ineffective. He also had developmental delay and a feeding tube, among other conditions such as the movement disorder choreoathetosis—a word that rolls off of Dalby’s tongue as naturally as it would for a specialist in the field. “It was very, very grim,” she explains.
After four years of perseverance, including traveling the country to consult with physicians, which led mostly to dead ends, Connor received a diagnosis after a whole exome sequence performed at UCLA. The sequencing revealed a mutation in SCN2A—the gene encodes a sodium channel that, when mutated, is commonly associated with early-onset epilepsy and linked to autism and developmental delay. Dalby always felt that, “if we knew what the root problem was, then there would be a solution.”
Upon learning of the mutation, Dalby did what she had done before—she worked to find a treatment for Connor. This was in 2014, when very little was known about SCN2a. She researched, called doctors and scientists in the field, and even started a biotech company, RogCon Biosciences, with another parent of a child with an SCN2a mutation. The program has since been licensed out to a larger biotech company.
When you have a child like Connor who is suffering every day, explains Dalby, and no doctor knows what to do and there is no medication to help, there is no other choice but to try to create it yourself or try to find people who may have an idea of how to help.
In 2019, Dalby ran into Crooke at the TIDES conference in San Diego, a conference dedicated to oligonucleotide and peptide therapeutics, where he told her about the idea of n-lorem. Jumping on the opportunity, she applied to n-lorem. When she was told that her application needed a physician or principal investigator to be involved in the case, she knew who to call.
Treating patients previously untreatable
Joe Gleeson, M.D., a child neurologist at Rady Children’s Hospital, had not heard of n-lorem before he was contacted by Dalby to nominate Connor’s case. One reason, he thinks, is because no cases had been documented at that time. He also asserts that patients are much more in tune to what’s going on than doctors.
Gleeson spent much of the first half of his career having no answers for patients who were desperate for them. That started to change about ten years ago, when the next-gen sequencing arena began to make an impact in the ability to diagnose children presenting with a spectrum of brain diseases—autism, epilepsy, intellectual disability, and more. There has been a big push since then to diagnose more children.
What has been missing, Gleeson explains, is a way to advance that knowledge to treatment. Because repurposing small molecules has proven difficult, gene therapy has garnered interest. Ionis’s success with an ASO for spinal muscular atrophy (SMA) opened up the possibility of treatments for genetic diseases. However, SMA is a disease where many patients with the same gene mutation could benefit from the same drug. N-lorem’s focus, in contrast, is developing ASOs for diseases where the number of children who could benefit is exceptionally low—as low as one.
Gleeson says that it was Mila Makovec’s case, which garnered international attention, that “really started to capture people’s imagination” because she was the first person in the world to receive an n-of-1 treatment approved by the FDA. After receiving a diagnosis of the fatal neurodegenerative disorder Batten’s Disease, Mila’s mother, Julia Vitarello, launched the effort, led by Yu in Boston, that resulted in the ASO treatment for Mila. The drug, named Milasen (after Mila), was a first in every respect, making it, and Mila, a poster child for hyper-personalized medicine.
Yu detailed the development of Mila’s ASO therapy in the article entitled, “Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease,” published in the New England Journal of Medicine in October 2019.
N-lorem’s work, to Gleeson, opens up the possibility of “treating conditions that we never thought were going to be treatable” and “learning which conditions could have paths forward.”
Now, Gleeson is part of n-lorem’s “access to treat” committee, a group of about ten physician-scientists who voluntarily meet once a month to review cases. Based on the clinical and genetic information, they recommend cases to be accepted by n-lorem. According to Gleeson, this is one of the most ethically challenging situations he has experienced.
Thankfully, he notes, Crooke’s generosity has eliminated the need to decide between two cases that could equally benefit. But, with more cases, he thinks that they will reach this point very quickly.
One concern for Gleeson is that, despite n-lorem’s valiant effort, they won’t be able to scale to the potential demand that exists. He thinks that as more families hear about n-lorem, and genetic diagnoses continue to increase, philanthropy is going to have to step up. Gleeson also worries about the wealthy having preferential access to these types of therapies.
Crooke is “reasonably optimistic” that n-lorem can raise the money needed to scale. Even in 2020, a tough year for fundraising, n-lorem raised several million dollars in donations.His greatest fear is that “we have to tell a patient we can’t treat them because we don’t have the money.” One way that Crooke is trying to prevent that from happening is by being very careful with n-lorem’s money. The foundation has one paid employee, there are roughly 70 volunteers from Ionis, and the rest of the team works for free. Crooke says that, with the growing case load, there are more people being brought on as consultants or part-time. But he asserts that “the dollars are limited, and I want those dollars to go to patients.”
It’s about the mutations, not the disease
We spend a lot of time in medical school, notes Gleeson, learning how to diagnose patients and which pathways are involved in which diseases. But n-lorem has taught us that it’s not so much the disease or even the gene, he explains, it’s the mutation type that is critical.
“You have to adjust your thinking,” Crooke asserts, explaining that people incorrectly think that the names of diseases mean something. But most of the names are archaic; they were coined hundreds of years ago based on what someone looked like when they were sick. Once you know the genetic cause of a disease, he notes, the name of the disease is completely irrelevant. At n-lorem, they care “about the genetic cause and if its fixable,” notes Crooke.
There are two major types of mutations in rare disease—gain of function (GOF) and loss of function (LOF). ASOs work well on GOF mutations, Gleeson says, because you can turn the gene off. It doesn’t work on LOF because a “dead gene” cannot be fixed using this technology. Certain rare mutations produce a new splice site that ends up silencing a gene. In such cases, an ASO could cloak the splice site, allowing the gene to splice normally. These mutations are prioritized at n-lorem because there is a path forward with ASOs.
Jumping through regulatory hoops
In addition to thinking about medicine in a new way, Gleeson is also learning about government regulation. These treatments require filing FDA applications—something he has never done before. According to Gleeson, this is a new issue for the medical field. “There’s not an experience,” he notes, “going back to Aristotle and Hippocrates, where there was a treatment for only one person.” It puts medicine in a completely different dimension, he adds, as the entire medical field, up till now, has been trying to find drugs that work in general for a disease class.
“We knew,” Crooke notes, “that this would test every edge of the regulations.” He did some of the work on this topic in 2019, because it is so critical, through “many interactions with the senior leaders of the drug division of the FDA and the policy people and various divisions.” He reports that they were interested and supportive; they care about these patients; and want to see something done. But the guidance surrounding this new space is “challenging,” Crooke notes.
FDA published initial guidance on January 4, 2021, to “Provide Clarity on Developing New Drug Products in the Age of Individualized Medicine.” Crooke says the fact the guidance was ASO-specific, positive, and emphasized collaboration, were all positive signs. Certain items that he would like to see in the official guidance (expected later this year) include immediate and early conversations as soon as a patient is identified, very limited pre-clinical work, and quality systems in place. He also proposed a partnership with n-lorem, with an FDA member on the access to treatment committee or the board, something he thinks is unlikely to occur. Crooke is looking forward to the guidance and is pleased with the progress so far.
From Gleeson’s perspective as a clinician, he hopes that FDA “can turn the applications around quickly.” Once the drug is ready, he notes, “we don’t want to have a long lag until it can actually be given to the patient because it’s not going to benefit anyone else.” By quickly, Gleeson means weeks.
Hard to put into words
For 11 years, Dalby has heard the same message—there is not much hope for Connor, and nothing can be done. N-lorem’s message could not be more different. Dalby, who tells Clinical OMICs that she is typically not a very emotional person, is moved when she speaks about n-lorem. “There is nothing in my entire life that has been this exciting up until now—this possibility that n-lorem holds for Connor,” Dalby says.
The mere idea, she explains, that there is a team of people fighting for him, to make a medicine just for him, is “so hard to put into words,” she says, “because it just makes my heart feel massive.”
Today, as Dalby waits for the ASO to be ready—which Crooke says takes about one year—she continues her work to help Connor. Her efforts today revolve around defining and cataloging Connor’s behaviors. This will help Gleeson and colleagues to design assessments and scales to monitor improvements after treatment.
Today and tomorrow
This work, for Gleeson, has implications now and for the future. The first purpose is to help the child. The second is “to teach us which diseases are reversible, because we don’t know.” One of Gleeson’s cases is a child with the lethal disease Cockayne syndrome. The mutation should be fixable with an ASO. There is “no doubt about that,” notes Gleeson. But it is unknown how much resiliency there is in the disease and the degree to which Cockayne syndrome can be reversed—something that will be learned from this case. This appreciation for today’s work and tomorrow’s hope was expressed by Mila’s mother, in a January 2018 blog post—the night before Mila’s first ASO treatment. Vitarello wrote that she was in a spot “between hope’s edge and a miracle.” She continues:
“Tomorrow, Mila will receive an injection of a new medicine that will go directly to her brain. It is experimental, which means it could be that breakthrough treatment that makes the impossible become possible. Or it could be a valiant attempt that just falls short. She could be the pioneer whose life is saved, or the one whose sacrifice helps those that follow.”
Mila passed away on February 11, 2021. Her mother’s blog post the next day read, “I always knew you were bound to do big things in life, but never did I imagine you would impact so many of us around the world in the way that you did.”
ASOs have been used in just a handful of cases. How does Dalby feel about Connor being a pioneer? “Completely exciting,” Dalby tells Clinical OMICs. When asked if she ever has reservations, Dalby quickly answers, “No.” She affirms, “not even for a second.”
“I know what his life is like today,” Dalby says. “We’ve tried all the available medications for all the different symptoms he has, and it hasn’t really helped him at all. I know what his life is going to consist of—I see it every day. So, this is nothing but hope and excitement.”
Taking care of a child with very severe medical complications can break you, she says. But the one thing that she has never let go of is the hope that “someone, somewhere, something is going to turn up and help Connor.”
When asked about the future of n-lorem, Crooke answers that he’s always been a big dreamer. Indeed, he had a big dream of creating RNA-targeted drug discovery when he started Ionis thirty years ago. In contrast, his dream for n-lorem is very small—one patient, one family at a time. If he can do that, he says, he will have done his best and “that’s enough.” Crooke adds, “I’m hopeful that at the end of this, we have enough money to meet the next family’s needs, and that’s the extent of my dream.”