Medical treatment designed for one patient may be the future for many

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Imagine you or your child gets a diagnosis so rare no one else on Earth is known to have it.

Doctors can do nothing but predict a terrible downward spiral followed by death.

That’s the situation Luke Rosen and Sally Jackson found themselves in when their daughter Susannah was diagnosed in 2016 with an ultra-rare genetic condition.

They were told their daughter, who has a mutation in a gene called KIF1A, had about five years before her condition would begin affecting her beyond repair. At year six, they met a man named Stanley Crooke who promised to develop a medication just for Susannah.

“Right on the brink of hopelessness, we knew that Susannah could possibly and hopefully have a different life,” said Rosen, a firefighter and former actor in Long Island, New York.

Now, after a year of an experimental treatment, the results are even better than they could have wished for.

Susannah is at the vanguard of a new movement in medicine: therapy so specialized it is designed for just a few patients, or even a single one.

Such bespoke therapies are possible because of advances in medicine including gene therapy, the messenger RNA approach used in COVID-19 vaccines, and a technology Crooke spent decades developing called antisense oligonucleotide, or ASO.

While an mRNA vaccine targeting a patient’s cancer is in the works and gene therapies are being designed to tackle rare diseases, for children with ultra-rare diseases like Susannah, the best approach at the moment is an ASO targeting a 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 have been unsuccessful at saving the children’s lives, Yu hopes the lessons learned from them will lead to better outcomes for others.

He helped found an international organization, called N=1 Collaborative, with hundreds of clinicians, researchers, patients and companies focused on individualized medicines.

For his part, Crooke has set up a nonprofit called n-Lorem to design drugs for people with ultra-rare genetic diseases. He aims to eventually treat thousands of patients, producing enough medication with the hope that each will live a much longer and healthier life.

More than 230 patients, about two-thirds of whom are children with devastating prognoses, have already applied to n-Lorem through their parents or doctors to receive a treatment. The foundation is getting ready to treat its sixth patient.

“I hope to change the world one patient at a time,” Crooke said in an interview recently.

Challenges of bespoke therapies

The first disease to prove the usefulness of ASOs was called spinal muscular atrophy. Dr. Wendy Chung remembers watching babies weaken and die, half of them before their first birthdays.

Crooke, then head of a company called Ionis Pharmaceuticals, spent 27 years developing the technology and steering it toward SMA. The drug, nusinersen, which was approved in late 2016, completely transformed the disease. The first children treated are now in middle school.

But ASOs won’t work in every disease, Chung said. It has great promise in diseases like SMA and other neurological conditions, but it has not proven as effective against other diseases, and it’s not clear how generalizable it will be. “Therein lies the rub,” she said.

Chung, who recently moved to Boston Children’s Hospital from Columbia University, sees four main challenges with such bespoke therapies: finding the right match between disease and treatment; delivering the treatment to the right place in the body; getting it made quickly enough to provide benefits; and doing no harm in the process.

“It’s complicated,” Chung acknowledged. But still, the potential to treat diseases that until now have had no options is “wonderful,” she said.

Safety is a top concern for individualized therapies.

Unlike treatments for common diseases, which are tested in thousands or tens of thousands of people before being marketed, ultra-rare disease patients and cancer patients may be the first to get their precise treatment.

One way to improve safety, Yu said, is for people trying this kind of bespoke therapy to share their data.

The N=1 Collaborative ‒ named for the idea that the number of participants in each drug study is just one ‒ is trying to standardize the way data is collected so it can be more easily shared and studied.

“We think there are going to be important learnings from aggregating all these cases,” Yu said in a call recently.

An ASO Yu developed for two toddlers with a lethal form of epilepsy led to hydrocephalus, or fluid on the brain. One of the two, a girl named Valeria, for whom Yu had named the ASO valeriasen, died.

He hopes lowering the dosage will help reduce the risk of hydrocephalus.

But it’s impossible to entirely remove the risk.

“Right now, we have a pristine safety record,” Crooke said of n-Lorem’s handful of patients. “My goal is to be able to say that five years from now, 10 years from now.”

Perhaps an even bigger challenge than creating a safe treatment is creating one that works in time.

In 2017, Yu designed an ASO he named milasen for the young girl, Mila, he hoped to save with it. Unfortunately, by the time he learned of her illness and delivered the drug to her a year later, her Batten disease, a disorder that causes seizures, lack of coordination and blindness, was advanced. Although the drug reduced her seizures and improved her quality of life, Mila died in February 2021.

With progressive diseases like Mila’s Batten and Susannah’s KIF1A, the biological clock ticks loudly. Once they are lost, brain and other nerve cells can’t be restored.

Crooke hopes that by the end of next year, he’ll be able to make an ASO for a patient within 15 to 18 months.

Still, he said, “an uncertain future is a heck of a lot better than a certain one.”

Looking for a future

Sloane Hedstrom, of Phoenix, was diagnosed with a KIF1A mutation at age 7 months.

The work the Rosen-Jacksons had done to raise awareness about 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 Susannah’s ASO should work for Sloane, too.

“I like to daydream and think about the really amazing things that could happen” if she gets the treatment, her mother Megan said in a Zoom call.

But realistically, there are a lot of unknowns.

“We don’t know what to expect and how safe it is,” Sloane’s grandfather Tom Lowe said on the video call. “The doctors and Stan (Crooke) are so careful about this, but still, you worry.”

For now, Sloane, who is 2½, is doing well. She isn’t troubled by seizures and she gets therapy every morning for her movement difficulties.

Her older siblings, ages 5 and 7, know that Sloane has special needs and has to go to the East Coast sometimes so doctors can watch over her and keep her healthy.

Thanks to a lot of family support, including a dad with a good job, full-time grandparents down the street, two aunts nearby and Megan’s “super-flexible” work in investment real estate, all three kids get the attention they need.

“These families that don’t have that kind of support, I don’t know how they do it,” Lowe said.

Sloane is still waiting for her therapy, though, because the drug needs to be filled and finished – put into vials in a sterile environment. N-Lorem foundation doesn’t have its own manufacturing facility, so it depends on the small number of such facilities in the United States. The foundation hopes to have the drug available within a few months.

Still, Lowe said, the pace of progress is impressive.

“It’s just remarkable what’s going on right now. It’s like this overnight success that’s taken 30 years of devotion to get to,” he said, tearing up. “I just want to stress how grateful we are.”

Scaling up

Financially, it’s challenging but not impossible to come up with the money for an ASO treatment, Crooke said.

His success with spinal muscular atrophy led to positive attention that has helped him raise donations. A recent n-Lorem meeting was sponsored by the biotech giant Biogen, which sells that earlier drug and was held in its offices in Cambridge, Massachusetts.

Although recently approved gene therapies are being marketed for several million dollars apiece, a lifetime supply of an ASO should be feasible for about $700,000, Crooke said, though it still costs more for now.

“Seven hundred thousand dollars to save a life and give someone a future and change the trajectory of a family, that’s a pretty good return on investment,” he said.

Treatments designed for single people or tiny populations don’t have to undergo the rigorous (and costly) testing process of drugs intended for larger groups. And once the general platform has been established, it should be relatively straightforward to make small changes needed to address a specific gene mutation or missing protein.

If it turns out that, as with Susannah and Sloane, more people are found to be treatable with the same ASO, the development costs can be spread over more patients or even recouped from insurance companies, Crooke said.

And treatments that address the root cause of disease can save money in the long run, experts say, by avoiding hospital stays and costly medications that treat symptoms but not the underlying disease.

Rosen said his and other families stand to save huge sums if they can wean children like Susannah off expensive medications with horrible side effects that “she probably doesn’t need anymore” anyway, and avoid painful, costly surgeries and adaptive equipment.

Rare diseases are rare on their own, but combined as many as 10% of Americans carry one of about 10,000 conditions considered “rare.”

Although the proportion affected by ultra-rare conditions is much smaller, they can offer insights into biological processes that can’t be understood otherwise, experts say.

“With these patients, biology is simplified for us,” Crooke said.

Unexpected progress

One morning shortly after her ASO treatment began, Rosen and Jackson, a member of Chef Bobby Flay’s executive team, realized it was really working for Susannah.

While Jackson and Susannah sat on the floor stretching, Rosen trained his phone’s camera on them.

“I’m going to teach you to stand up,” Susannah announced before getting up from the floor independently for the first time in several years. The treatment, Rosen realized through joyful tears, was reversing her disease, not just slowing its progression.

She can use a spoon now, feeding herself without her hand shaking so much that the food falls off. She wakes up without big, dark circles under her eyes, not soaked in sweat or shaking. She has the energy to make it through a full day of school, getting more from her lessons and therapies.

This summer, Rosen ran a 5K honoring those who had died in the 9/11 attack on New York, pushing Susannah in a wheelchair. Near the end, she pulled the brakes, and with her 12-year-old brother, Nat, crossed the finish line under her own power.

“It was a choice she made,” Rosen said. “She’s making choices now. … That, to our whole family, is a gift beyond measure.”

The difference has transformed their home life. Rosen and Jackson can talk to each other at dinner and ask Nat about his day at school “rather than be on edge,” always worrying whether Susannah is about to choke on her food and require the Heimlich maneuver.

The girl who couldn’t string a sentence together can now say age-appropriate things like “easy peasy lemon squeezy,” Rosen said.

And best of all, Susannah’s not in as much pain.

Although he felt terribly guilty, Rosen said, he used to leave the room while Jackson calmed Susannah as she wailed from the pain caused by her dying nerves. He couldn’t take it. There’s no more hopeless feeling as a parent than not being able help, he said.

Now, all their lives have been transformed. And they hope Susannah’s success is just the beginning for families with rare diseases.

“This trial, these unknown waters for her disease, is terrifying for us, but the elation we feel when we see her progress and her smile is beyond measure,” Rosen said. “That’s how to measure the risk/benefit of an experimental ASO − by Susannah’s smile.”

Contact Karen Weintraub at kweintraub@usatoday.com.

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