With COVID vaccines in the news on a daily basis, the average person is more familiar with the process of drug trials than ever.
Months if not years of drug development. Thousands of people in trials for months more. FDA panels for approval, and even that was accelerated with federal funding and fast-tracking because of the pandemic.
But what if you’re the only person in America with your disease? What hope would you have of finding a treatment?
Western Associate Professor of Psychology Jeff Carroll hopes to be part of solving that issue, and is working on the treatment committee of nonprofit n-Lorem to help connect patients with ultra-rare diseases with individualized treatment.
“There’s this constraint. You can do the math. There have to be X number of patients in order to sell (a drug) for Y dollars to be able to make back the hundreds of millions of dollars it cost. That’s just not feasible for a disease that effects under 10 people around the world,” he says. “They have the same ethical claim for getting care that we do. People should care about them just as much. There just hasn’t been a mechanism for it.”
That’s where n-Lorem comes in.
The nonprofit was started by Stan Crooke, the founder of Ionis Pharmaceuticals, which has worked on antisense treatment technology for decades and now has treatments in large human studies, including several for neurodegenerative disorders such as ALS. After retiring from Ionis, Crooke started n-Lorem with the goal of setting up similar treatments for the kinds of ultra-rare cases that lack the number of patients for full trials and the financial incentive for a company to develop a drug.
The patients n-Lorem can help are those whose genetic mutations could be treated by antisense therapy, which uses antisense oligonucleotides or ASOs, short strands of modified DNA that can specifically target a defective gene. ASOs are designed to bind with RNA and stop the process of creating a disease-causing protein, disrupting the disease. This treatment is being developed for more common diseases such as genetic forms of ALS, but it can be applied for ultra-rare genetic diseases as well. For each ultra-rare case that is selected, patients will have their genome sequenced to confirm their causal mutation, and then n-Lorem’s scientists will develop and test ASOs to see which will work to modify the functions of the mutant RNA, hopefully halting or slowing the disease process.
Carroll started working with Ionis in 2006 while getting his doctorate, working specifically on developing ASOs and testing them in mouse models for Huntington’s Disease. Carroll applies those lessons now as he runs the Carroll Lab for the Neurobiology of Huntington’s Disease at Western. His previous connections and work at Ionis led n-Lorem board members to reach out to him to join the access to treatment committee, and since then it’s been an incredible process of learning as each new case comes in.
Every day or couple of days now I’m learning about an entirely new genetic disease with a different mechanism.
“From my point of view, I’ve learned so much. Every day or couple of days now I’m learning about an entirely new genetic disease with a different mechanism,” Carroll says. “It’s very humbling because I thought I was a reasonably smart guy.”
The nonprofit is still in its early days, with about 40 patients at various stages of the process. The first is on the cusp of receiving treatment: a pre-teen boy who suffers from a debilitating seizure disorder. While helping patients with ultra-rare diseases is the mission and is important in and of itself, each patient helped also helps n-Lorem and its scientists improve the process for future patients being treated.
“We’ll learn how to treat other ultra-rare diseases better. We’ll learn better ways of delivery, better ways to work with the doctors, better ways to work with the hospitals to get permission,” Carroll says. “All that simple stuff that ends up being troublesome in the real world, we’ll figure those processes out as we go along.”
How it works
Patients with ultra-rare diseases caused by genetic mutations that affect fewer than 10 people around the globe can apply to n-Lorem for treatment, either themselves or through their physician or a caregiver. Carroll reviews those applications — along with Joseph Gleeson, professor of neurosciences and pediatrics at the University of California at San Diego, and National Institutes of Health neurogenetics branch investigator Kenneth Fischbeck — to see if they would be a match for the antisense treatment that n-Lorem specializes in. If they are, and they are approved by n-Lorem’s Access to Treatment and Executive committees, n-Lorem scientists get to work finding the right therapy to address the mutation.
“For some of these cases, it’s so clear that this mutant gene is causing this problem, and I’m so optimistic that ASOs can work,” Carroll says. “We’ve seen them work in many other conditions now. It’s just putting two and two together and seeing what happens. I think it would be crazy to think every single one of these cases will have a sudden dramatic reversion where a person will just not be affected anymore, but I think we can make a really significant impact on most or ideally all of these people.”
So far, patients who have been selected have run the gamut as far as age and disease goes, with many pediatric cases for neurological issues and seizure disorders. As a parent himself, those pediatric cases hit close to home.
“Just thinking about that parental journey, of the elation that the baby’s here and taking them home, and then the progressive horror that develops as you realize that not only is something just a bit off but something quite bad is happening with their newborn, who otherwise looks healthy,” Carroll says. “Those ones are really hard for me as a parent to imagine what that’s like for those families.”
Patients include adults as well, whose disease may have shown up later in life and proved arduous to nail down. Examples include genetic mutations that lead to steadily degrading vision and eventually blindness or forms of ALS caused by ultra-rare genetic mutations.
“A lot of people go through — genetic disease families call it a diagnostic odyssey — of often years of ‘there’s something off’ or ‘there’s something wrong’ with themselves or a loved one, and going through the rigamarole of different doctors and different specialists, and it can be quite a journey,” Carroll says of adult-onset cases. “And because these things are so rare, no physician is going to know about them right off the bat.”
To get around the need for the kind of large-scale trials that aren’t possible for ultra-rare diseases, n-Lorem works with each patient’s physician, and the doctor files an investigator-initiated Investigational New Drug application that would allow their patient to take the drug that n-Lorem creates. This accelerated option provides a pathway for FDA approval as long as there is evidence the drug is not toxic – n-Lorem uses animal models for safety testing – and a reasonable biological reason to think the ASO will make the patient better. The staff at n-Lorem supports the physician throughout the application process, and following approval, n-Lorem provides the physician a free lifetime supply of the patient’s treatment.
“A lot of these physicians have been super keen,” Carroll says. “A lot of them have been seeing various genetic diseases forever and never really been able to do anything about it or offer anything to their patient, so by and large they’ve been pretty excited about it.”
A new era in human genetics
The work Carroll and n-Lorem are doing is possible because of the advances that have occurred in genome sequencing and figuring out causal mutations. Scientists for n-Lorem complete whole-genome sequencing for patients as part of the process of identifying the disease-causing mutation. Using that sequencing to not only find a cause for a disease, but a treatment as well could be a medical game-changer.
“We’re at a relatively early phase of this, but it’s super exciting,” Carroll says. “It’s so exciting to transition the era of human genetics as a time when you can find out what is wrong with people, which is super powerful and useful but limited, to potentially being able to actually do something about it. It’s really rewarding and exciting to be a small part of that broader shift that’s happening.”
Because these things are so rare, no physician is going to know about them right off the bat.
While Carroll describes n-Lorem’s work as trail-blazing, it’s not alone in the field. Other nonprofits and businesses are starting to work on gene editing and gene therapy treatments that could help patients with ultra-rare diseases as well.
“My sort of fantasy is that someday there would be multiple n-Lorems with different skillsets, and that we’d be screening people early enough to catch these things before they start to cause problems -- and swoop in with the right intervention,” he says.
Carroll’s experience learning about patients and their genetic mutations has allowed him to bring more real-world examples to his classes, helping students to make better connections between the neuroscience concepts he’s teaching and how they can affect real people — and more than they might think.
“If you count up all the people who have ultra-rare diseases, it’s not ultra-rare at all; it’s quite common. There’s an awful lot of people with these diseases out there, and it’s amazing to think about a zoo of organizations like n-Lorem being able to address different segments of those population,” he said. “This effort is the most advanced effort to try to give people affected by ultra-rare mutations some comfort and some compassion. It’s really exciting to be part of that and rewarding in a different way.”