Imagine if you or your child had a diagnosis so rare that no one else on earth had it.
Doctors can do nothing but predict the terrible downward spiral that will follow death.
In the year That’s the situation Luke Rosen and Sally Jackson found themselves in 2016 when their daughter Susanna was diagnosed with an extremely rare genetic disease.
They were told their daughter, who had a mutation in a gene called KIF1A, had it five years before her condition began to irreparably affect her. At the age of six, they meet a man named Stanley Crook, who promises to make a cure just for Susanna.
“On the brink of despair, we knew Susanna would probably have a different life,” said Rosen, a firefighter and former actor in Long Island, New York.
Now after a year of experimental treatment, the results are better than expected.
Susanna is on the lookout for a new movement in medicine: therapy that is very specifically designed for just a few patients or a single individual.
Such fake treatments are possible thanks to advances in medicine, including gene therapy, the messenger RNA approach used in Covid-19 vaccines, and a technology known as crooked antisense oligonucleotides, or ASOs, that has spent decades in research.
While an mRNA vaccine targeting a patient’s cancer is being developed and gene therapies are being designed to address rare diseases, the best approach for children with extremely rare diseases like Susana’s is currently an ASO for the protein involved in that patient’s disease. .
Dr. Timothy Yu, of Boston Children’s Hospital, was the first to treat a child with an ASO designed specifically for her. Although some ultimately failed to save the children’s lives, Yu hopes the lessons learned from them will lead to better outcomes for others.
The N=1 Collaborative, a global organization focused on individualized medicine, has helped hundreds of clinicians, researchers, patients and companies.
Crook, meanwhile, founded a non-profit organization called En-Lorem, which designs drugs for people with extremely rare genetic diseases. He plans to produce enough medicine to eventually treat thousands of patients, hoping that each one will live a long and healthy life.
More than 230 patients, 2/3 of them children with a terrible prognosis, have already been referred to n-Lorem by their parents or doctors for treatment. The foundation is preparing to treat the sixth patient.
“I hope to change the world one patient at a time,” Crook said in a recent interview.
Challenges of mandatory treatments
The first disease to prove the usefulness of ASOs is called spinal muscular atrophy. Dr. Wendy Chung remembers watching babies languish and die, half before their first birthday.
Crook, then head of Ionis Pharmaceuticals, spent 27 years developing the technology and leading the way toward SMA. In the year The drug Nusinerson, which was approved at the end of 2016, completely reversed the disease. The children who received the first treatment are now in middle school.
But ASOs don’t work on every disease, Chung said. It has great promise in diseases such as SMA and other neurological conditions, but its effectiveness in other diseases has not been proven, and it is unclear how general it will be. “There’s a rub in this,” she said.
Chung, who recently transferred from Columbia University to Boston Children’s Hospital, sees four main challenges with such predictive therapies: finding the right match between disease and treatment; delivering the treatment to the right place in the body; Act quickly to deliver benefits; And it doesn’t cause any harm in the process.
“It’s complicated,” Chung said. But its potential to treat diseases for which there are currently no options is “remarkable,” she says.
Safety is a major concern for individual therapies.
Unlike treatments for common diseases, which are tested by thousands or tens of thousands of people before they go to market, patients with extremely rare diseases and cancer can be the first to receive the right treatment.
One way to improve safety, Yu said, is to get people trying such oral treatments to share their data.
N=1 Collaboration—named for the idea that the number of participants in each drug study is only one—is trying to make data collection easier to share and study.
“We think there will be important lessons from bringing all these issues together,” Yu said on a recent call.
An ASO developed for two teenagers with life-threatening epilepsy led Yu to develop hydrocephalus, or fluid on the brain. One of the two, a girl named Valeria, whom the U.A.S.O. named Valeriacene, died.
He hopes that reducing the dose will help reduce the risk of hydrocephalus.
But the risk cannot be completely avoided.
“Currently, we have a good safety record,” Crook said of n-Lorem’s handful of patients. “My goal is to be able to say this in five years, 10 years from now.”
Perhaps a bigger challenge than creating a safe treatment is creating one that works in time.
In the year In 2017, he developed an ASO, which he named Yu Milason, for the young girl Mila, whom he hoped to save. Unfortunately, by the time he diagnosed her condition and administered the medication a year later, her Batin’s disease, which causes seizures, loss of coordination and blindness, had worsened. Although the drug reduced her seizures and improved her quality of life, Mila died in February 2021..
In progressive diseases like Mila Batten and Susannah’s KIF1A, the biological clock is ticking loudly. Once lost, the brain and other neurons cannot be restored.
Crook hopes to be able to work on a patient ASO within 15 to 18 months by the end of next year.
Still, he said, “an uncertain future is much better than a certain one.”
Looking for the future
Sloane Hedstrom of Phoenix was diagnosed with the KIF1A mutation at age 7 months.
Rosen-Jackson’s work to raise awareness of KIF1A led to a relatively rapid diagnosis, giving Sloane a two-year head start on most other children with the disease.
About a year later, the Hedstroms learned that Susannah’s ASO should also work for Sloane.
“I love daydreaming and thinking about the amazing things that could happen,” said her mom, Megan, on a call highlighting her treatment.
But in fact, there are many unknowns.
“We don’t know what to expect and how safe he is,” Sloane’s grandfather, Tom Lowe, said in a video call. “The doctors and Stan (Crook) are very careful about this, but you still worry.”
For now, Sloane, who is 2½, is doing well. She does not suffer from epilepsy and receives treatment for movement disorders every morning.
Her older siblings, ages 5 and 7, know Sloane has special needs and needs to go to the East Coast sometimes to keep doctors safe and healthy.
Thanks to a lot of family support, a dad with a good job, full-time grandparents on the way, two aunts nearby, and Megan’s “super flexible” job in investment real estate, all three kids get the attention they need.
“I don’t know how these families do it without that kind of support,” Lowe said.
Sloane is still waiting for her therapy, but because the medicine needs to be filled and completed – put into bottles in a sterile environment. N-Lorem Foundation does not have its own manufacturing facility, so it is based on a small number in the United States. The foundation hopes that the drug will be available in a few months.
Still, Lowe said, the pace of growth is impressive.
“It’s amazing what’s happening right now. It’s such an overnight success that took 30 years to achieve,” he said through tears. “I want to emphasize how grateful we are.”
Raise up
Financially, coming up with the money for ASO treatment is challenging but not impossible, Crook said.
His success with spinal muscle ablation brought positive attention that helped boost donations. A recent n-Lorem meeting was sponsored by biotech giant Biogen, which sells that early drug and was held at its offices in Cambridge, Massachusetts.
Although recently approved gene therapies are being marketed for several million dollars each, a lifetime supply of ASO should cost about $700,000, Crook said, although it still costs more for now.
“Seven hundred thousand dollars to save a life and give someone a future and change a family’s situation is a very good return on investment,” he said.
Treatments designed for individual people or small populations do not have to go through the rigorous (and expensive) testing process of drugs intended for large groups. And once the overall platform is established, it should be relatively straightforward to make the small changes needed to address a specific gene mutation or missing protein.
If, like Susanna and Sloane, it is proven that more people can be treated with the same ASO, the cost of development could be spread over more patients and even reimbursed by insurance companies, Crook said.
And treatments that address the underlying cause of the disease can save money in the long run, experts say, by avoiding hospitalizations and expensive drugs to treat symptoms that don’t cure the underlying disease.
Rosen said he and other families stand to save a lot of money if children like Suzanne’s can be weaned off expensive drugs from painful side effects and “doesn’t need her anymore” and avoid painful, expensive surgeries and fitting equipment.
Rare diseases themselves are rare, but up to 10% of Americans have one of the 10,000 diseases that are considered “rare.”
Although the extent of damage in extremely rare cases is very small, it can provide insights into biological processes that cannot be understood otherwise, experts say.
“In these patients, the biology is simple for us,” Crook said.
Unexpected growth
One morning after her ASO treatment began, Rosen and Jackson, members of chef Bobby Flay’s executive team, realized it was indeed working for Susanna.
As Jackson and Susannah lay on the floor, Rosen trained his phone camera on them.
“I’m going to teach you to stand,” Susanna said before getting up off the floor on her own for the first time in years. The treatment, says Rose in tears of joy, is reversing her pain, not slowing its progression.
Now she can use a spoon, feeding herself without shaking her hand too much, the food falls. She wakes up without big, dark circles under her eyes, drenched in sweat, and shaking. She has the energy to get through a full day of school, getting more out of her classes and treatments.
This summer, Rosen ran a 5K in honor of those who died in the 9/11 attacks in New York, pushing Suzanne in a wheelchair. Near the end, she pulled on the brakes and crossed the finish line under her own power with her 12-year-old brother, Nat.
“It was her choice,” Rosen said. “She’s making choices now. … That’s an overwhelming gift for our whole family.”
The difference changed their home life. Rosen and Jackson can talk to each other over dinner and question Nat’s time at school “rather than on the sidelines,” always worried that Susanna will choke on her food and need the Heimlich maneuver.
The girl who couldn’t string a sentence together can now say age-appropriate things like “easy pea lemon squeeze,” Rosen said.
And best of all, Susanna isn’t in as much pain.
Although he felt very guilty, according to Rosen, he was leaving the room, when Jackson calmed Susanna, who was crying from the pain of her dying nerves. He couldn’t take it. As a parent, there is no greater feeling of despair than not getting help, he said.
Now all their lives have changed. And they hope Suzanne’s success is just the beginning for families with rare diseases.
“This trial, these uncharted waters for her disease, are very scary for us, but the joy we feel seeing her progress and her smile is overwhelming,” Rosen said. “How to Measure the Risk/Benefit of Experimental ASO – By Susanna Smiley.”
Contact Karen Weintraub at kweintraub@usatoday.com.
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