New drug fights neurological gene mutation

In 2016, when Susannah Rosen was 2.5 years old, her parents Luke Rosen and Sally Jackson noticed something was wrong during a bath. When Sally playfully told Susannah to kick her legs into the water, Susannah failed.

“If our first child had a bee sting, we’d be rushing to the emergency room, right? But we were thinking, he’s our second child, you know? He’ll catch up on his own… but he didn’t,” Luke said. “We went to the hospital after we found out he couldn’t kick.”

Luke and Sally were living in New York with their two children. Luke had a successful career as an actor and writer, and Sally was working as a chef’s assistant.

Luke said Susannah did not have very good balance as a toddler and needed help walking, which are common characteristics of a child learning a new milestone. But as time went on, the gap between Susannah’s development and that of her peers began to widen.

“He was couch surfing and army crawling around the apartment at an age when toddlers usually start running,” Luke recalled. When she tried to walk, Susannah had a wide gait and appeared unsteady and unstable; This was often a symptom of an underlying problem.

Susannah was diagnosed with a mutation in the KIF1A gene. The KIF1A gene takes its name from the important molecular motor protein it produces that 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 the KIF1A gene caused a “toxic gain of function”.

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

More than 90% of patients diagnosed with CAND have developmental delays and intellectual disabilities, more than 80% have vision loss or impairment, and more than 40% have seizures. Many people also experience other symptoms, ranging from diarrhea and constipation to kidney problems. Experts say no two patients are affected in the same way, making it very difficult to accurately diagnose the disorder. Accordingly KIF1A.orgApproximately 1 in 4 of those diagnosed with a KIF1A mutation were initially misdiagnosed with cerebral palsy.

When Susannah was diagnosed in 2016, there was no treatment available for KIF1A and no clinical trials or literature to rely on for answers. The Rosens were told Susannah probably wouldn’t be able to walk and would likely have a seizure.

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

Susannah’s doctor, Dr. Wendy Chung told the Rosens they had five years to find a cure for Susannah before it was too late. He suggested that Luke and Sally try to find 100 patients with the same diagnosis as Susannah so that they could begin to better understand the disease and how it progresses.

Luke and Sally started KIF1A.org foundation shortly after Susannah’s diagnosis. They hoped that by connecting with other families living with CAND, they could build a large enough patient population to initiate research that could eventually lead to the discovery of a treatment. Today the foundation has managed to connect 700 families hoping to race against time.

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

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

“The FDA defines rare disease 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 these patients because they have no hope. When you’re one of 30 people, you can imagine the isolation, the helplessness, and the lack of information available.”

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

Crooke said the foundation has received more than 400 applications from rare disease patients since its founding and has been able to accept about 200 of them. Once admitted, the patient was added to the waiting list, he said, and n-Lorem will soon begin treating the organization’s 40th patient.

But n-Lorem was just getting started when the Rosens learned of Crooke’s work. Chung approached 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 treatment is a spine procedure that removes fluid and replaces it with medication that targets the gene mutation. In Susannah’s case, ASO therapy allowed normal protein production.

“This is genetic medicine,” Crooke said. “So we take the genetic code directly and design a relatively small molecule of 18 to 20 genetic letters with the genetic ‘ZIP code’ that will direct it to the RNA in the cell that we want it to bind to. We can then engineer the ASO to do a variety of things: inhibit the production of a disease-causing protein, produce a better protein, or produce a protein that is not produced in sufficient quantities.”

He said that after Susannah’s second dose, Luke began to notice a difference in Susannah’s behavior.

“We were sitting at breakfast one morning after treatment and I said, ‘Something is wrong,’” Luke recalled. “But it wasn’t. It was quiet and we could look at each other. The tremors had gone away. It’s not an FDA-approved outcome measure or an end point, but it’s something that means the world to us. It still has its challenges and issues, but it’s just the tremors going away, a place where we can have breakfast together… that’s when I knew the medicine was working.”

Susannah has been receiving ASO treatment for three years, and the Rosens said they are grateful for the time given to them. But they know the road ahead for Susannah will likely remain challenging.

“We’re afraid the disease will catch up with the treatment. He’s regressing in some ways and I wish we had gotten him this treatment five years ago,” Luke said. “The next child [to receive the same treatment] He will be younger and the treatment will reach every brain cell… I know this. Our daughter is a pioneer. It is both heartbreaking and partly heart-warming. She’s gorgeous and tough as nails.”

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