New drug fights neurological gene mutations

In 2016, when Susannah Rosen was 2½ years old, her parents, Luke Rosen and Sally Jackson, noticed something was wrong while she was bathing. When Sally asked Susannah to playfully kick her legs in the water, she couldn’t do it.

“For our first child, if it was a bee sting, we’d run to the emergency room, right? But we thought she’s our second child, you know? She’ll catch up on her own…but she didn’t catch up,” Luke said. “After we found out she couldn’t kick, we went to the hospital.”

Luke and Sally lived in New York City with their two children. Luke had a successful career as an actor and writer and Sally worked as a chef’s assistant.

Luke said that as a toddler, Susannah had poor balance and needed help walking, typical characteristics of a child learning a new milestone. But over time, the gap between Susannah’s development and that of her peers began to widen.

Sally Jackson, Luke Rosen and their daughter Susannah Rosen

“She was couch surfing and army crawling around the apartment at an age when toddlers typically start walking,” Luke remembers. When she attempted to walk, Susannah had a wide gait and appeared unsteady and uncoordinated, which was often a symptom of an underlying problem.

Susannah was diagnosed with a mutation in her KIF1A gene. The KIF1A gene gets its name from an important molecular motor protein it produces, which is vital for brain function. Mutations in this gene cause KIF1A-associated neurological disorder, or KAND. When Susannah was diagnosed, Luke and Sally were told that the mutation in her KIF1A gene caused a “toxic gain of function.”

“When I heard that, I thought, ‘gain of function’. That’s good!” Luke said. “[But] it’s not good. The function that this gene performs releases this really toxic protein element that slowly kills the nerves in their brain and the nerves throughout their body.

More than 90% of patients diagnosed with KAND have developmental delays and intellectual disabilities, more than 80% experience vision loss or impairment, and more than 40% have seizures. In addition, many people experience other symptoms ranging from diarrhea and constipation to kidney problems. Experts say no two patients are affected in the same way, making proper diagnosis of the condition very difficult. According to KIF1A.org, about one in four people diagnosed with KIF1A mutations were initially misdiagnosed with cerebral palsy.

Sally, Luke and Susannah on a walk.

Courtesy: Rosen family

At the time of Susannah’s diagnosis in 2016, there were no treatment options for KIF1A and there were no ongoing clinical trials or literature to rely on for answers. The Rosens were told that Susannah probably wouldn’t be able to walk and would likely suffer seizures.

“So there were a lot of tears in that room,” Luke said. “This was the beginning of our incredibly new and terrible normal.”

Susannah’s doctor Dr. CNBC advisory board member Wendy Chung told the Rosens they have five years to find treatment for Susannah before it is likely too late. She recommended that Luke and Sally find 100 patients with the same diagnosis as Susannah so that they could begin to better understand the disease and its progression.

CNBC Heals Susannah Rosen and Dr. Wendy Chung

Courtesy: Rosen family

Luke and Sally founded the KIF1A.org Foundation shortly after Susannah’s diagnosis. They hoped that by connecting with other families living with KAND, they could build a large enough patient population to begin research that could eventually lead to a treatment discovery. Today the foundation was able to bring together 700 families who want to compete against time together.

“One of the things we noticed about KIF1A is that it’s not nearly as rare as we might think,” Chung said in a recorded interview with KIF1A.org. “We can see that the numbers have increased over the last three years.”

These efforts eventually led them to the n-Lorem Foundation. n-Lorem was founded in 2020 by Ionis Pharmaceuticals founder and CNBC Advisory Board member Dr. Founded by Dr. Stanley Crooke, Dr. Stanley Crooke is a nonprofit organization that develops antisense oligonucleotide, or ASO, therapies for patients with nanorare diseases and provides the treatments free of charge for life. “Nano-rare” is a term coined by Crooke to describe extremely rare diseases that affect between one and 30 people worldwide.

Susannah Rosen in the hospital for her ASO treatment.

Courtesy: Rosen family

“The FDA defines rare diseases as a patient population of 200,000,” Crooke said in an interview with CNBC. “But we now know that there are many, many pathogenic mutations that cause disease in far fewer patients… And our focus is on those patients because they have no hope. You can imagine the isolation, the despair and the lack of information that is available when you are one in 30.”

Crooke estimates he has personally spent $10 million developing new drugs and treating patients since 2020, a fraction of the amount the foundation has spent, he said. Patients with the same mutation can be treated with the same drug, but if n-Lorem needs to develop a new treatment, the average cost is $1.2 million, he said.

Since the foundation’s inception, there have been more than 400 applicants for rare disease patients, of which it has been able to accept about 200, Crooke said. Once admitted, the patient will be placed on a waiting list and n-Lorem will soon begin treating the organization’s 40th patient, he said.

But when the Rosens learned of Crooke’s work, n-Lorem had just begun. Chung applied to n-Lorem to develop a treatment for Susannah, and Susannah became n-Lorem’s first patient to be treated with an ASO therapy developed by the foundation.

ASO therapy is a spinal procedure in which fluid is removed and replaced with the drug that targets the gene mutation. In Susannah’s case, ASO therapy allows for normal protein production.

Sally Jackson and her daughter Susannah Rosen in a hospital bed

Courtesy: Rosen family

“It’s genetic medicine,” Crooke said. “So we take the genetic code directly and design a relatively small molecule, 18 to 20 genetic letters, with this genetic ‘zip code’ that directs it to the RNA in the cell that it is supposed to bind to. And then we can design the ASO to do different things: prevent the production of a disease-causing protein, produce a better protein, or produce a protein that is not produced in sufficient quantities.”

After Susannah’s second dose, Luke noticed a difference in Susannah’s behavior, he said.

“One morning after she was treated, we were having breakfast and I thought, ‘Something’s wrong,'” Luke remembers. “But that wasn’t the case. It was the fact that it was quiet and we could look at each other. Her tremors were gone. That’s not an FDA-approved outcome indicator or endpoint, but it’s something that just means the world to us. She still has her challenges and problems, but just the tremors go away so we can have breakfast together… that’s when I knew the medication was working.”

The Rosen family enjoys a meal together.

Courtesy: Rosen family

Susannah has been receiving the ASO treatments for three years and the Rosens said they are grateful for the time that has been given to them. But they know that the road ahead of Susannah is likely to remain difficult.

“We’re worried that the disease is catching up with the treatment. She’s regressing in some ways – and we just wish we had gotten this treatment for her five years ago,” Luke said. “The next child [to receive the same treatment] will be younger and the treatment will reach every brain cell… I know it. Our girl is a pioneer. It is both heartbreaking and at times heartwarming. She’s amazing and tough.”

To learn more about KIF1A-associated neurological disorders, visit Luke and Sally’s Foundation, KIF1A.org.