Leveraging rapid developments in gene therapy, researchers are designing new ways to target ultra-rare genetic diseases with treatments tailored to a patient’s specific genetic makeup. Such therapies are promising and potentially transformative for patients and their families. At the same time, several challenges exist in developing, delivering, and financing these highly personalized treatments.
The ASO Approach
Antisense oligonucleotides (ASOs) are short strands of modified DNA that can be engineered to target a defective gene. For example, the ASO drug nusinersen treats spinal muscular atrophy (SMA), a rare neuromuscular disorder, by modifying the SMN2 gene to produce increased survival motor neuron protein. Nusinersen was approved in 2016 and illustrated the transformative potential of the ASO approach, which can be customized for ultra-rare genetic diseases.
Stanley Crooke, as head of Ionis Pharmaceuticals, spent decades developing ASOs. He now operates a nonprofit, n-Lorem, to design and provide personalized genetic therapies at no cost to the patients. The organization has treated six patients and has received applications from more than 230 people. Creating customized therapies quickly enough to help children with advancing diseases remains challenging. Crooke hopes to reduce the time needed to make a personalized ASO to 15 months. Safety is another challenge that the nonprofit has met successfully so far. “Right now, we have a pristine safety record,” Crooke said of n-Lorem’s small number of patients. “My goal is to be able to say that five years from now, 10 years from now.”
Many Partners, One Goal
Because customized treatments may have only one recipient, collaboration across such efforts is critical to understanding risk and advancing research. Timothy Yu, a physician at Boston Children’s Hospital, helped found the N=1 Collaborative, an international nonprofit organization comprising clinicians, researchers, patients, and companies working together to advance individualized genetic therapies.
Without the usual clinical trial process to evaluate efficacy and safety, the group is working to standardize data collection for easier dissemination and analysis. “We think there are going to be important learnings from aggregating all these cases,” Yu said.
Navigating Financial Challenges
Crooke envisions a future where personalized treatments are more accessible, citing the estimated cost for a lifetime supply of an ASO. “Seven hundred thousand dollars to save a life, give someone a future and change the trajectory of a family, that’s a pretty good return on investment,” he said. He hopes to eventually be able to offer treatment to thousands of patients, extending their lifespans and improving their quality of life. “I hope to change the world one patient at a time,” he said.
Success Story
One patient’s story illustrates the promise of customized ASOs. At two years old, Susannah Rosen was diagnosed with an ultra-rare genetic disorder called KIF1A-associated neurological disorder, caused by mutations in the KIF1A gene. The disease causes seizures, pain and movement and vision problems. She is receiving an experimental ASO developed by researchers at n-Lorem and has shown significant improvement. She experiences less pain and has better movement control and energy.
When Sloane Hedstrom was diagnosed with a KIF1A mutation at age seven months, her family connected with n-Lorem. The researchers hope the drug designed for Susannah should also work for Sloane.
Although patients’ families appreciate the risk involved in experimental therapies, seeing a child improve is empowering. “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,” said Susannah’s father, Luke Rosen. “That’s how to measure the risk/benefit of an experimental ASO — by Susannah’s smile.”
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