Within the world of rare diseases exist conditions so sparse and infrequent they’re called nano-rare — or N of 1  — diseases and typically affect only one to thirty people worldwide (1). While less than 10% of rare diseases have approved treatments, nano-rare or ultra-rare diseases are often entirely excluded from drug development programs (1). However, the sphere of bespoke medicine is changing this, providing hope for families who once viewed their child’s disease as untreatable.

Susannah’s story: creating a personalized treatment

Susannah Rosen’s story begins when she was a baby, when her parents, Luke and Sally, put their daughter in a bathtub and noticed she couldn’t kick with her legs. As a toddler, Susannah would suddenly fall while standing and walking, making leg braces necessary. At age two, doctors found she was having seizures while she slept. Her childhood was spent in hospitals, with her parents and doctors watching as her untreatable disease gradually took away her ability to stand, walk, and see.

In 2016, she was diagnosed with KIF1A-associated neurological disorder (KAND), an untreatable and rare genetic mutation causing progressively worse developmental delays, vision loss, seizures, and physical disabilities. At nine years old, Susannah spoke in simple sentences with frequent pauses, had 100 to 290 seizures a day, and her many falls had caused multiple bone fractures and the need for a wheelchair (1).

After being advised by Susannah’s doctor — Wendy Chung — to find other patients with KAND, her parents started a foundation in 2017, found 400 people worldwide with the disease, raised $2 million for research, and started lobbying scientists to develop treatments.

In October 2022, Susannah was the first person in the world to receive a drug created to treat KAND, which was designed specifically for her. The bespoke therapy was paid for by n-Lorem, a nonprofit organization that aims to provide experimental antisense oligonucleotide (ASO) based treatments to patients with ultrarare diseases (1).

Susannah’s treatment: cognitive improvements and reduced seizures

It took 17 months for scientists at n-Lorem to create a drug to shut down Susannah’s specific KIF1A gene mutation, a missense variant reported in only eight people worldwide (1). Dr. Stanley Crooke, the founder of the pharmaceutical company Ionis and n-Lorem, explained in the press release that because the KIF1A protein serves a vital function in the body, their ASO design had to target the copy of the mutated gene while allowing the healthy copy not containing the mutation to produce normal KIF1A proteins.

“This selective gene targeting of the ASO allows the functional KIF1A protein to be expressed and available for normal cellular function while removing the toxic KIF1A protein,” Dr. Crooke stated.

Susannah grew sicker as they waited for the drug, but the day after her first dose, the girl woke up smiling. The nine-month treatment, which started at 20mg and was gradually increased to 80mg by day 301, was injected into Susannah’s spinal cord. Besides an initial complication of an epidural cerebrospinal fluid collection, which resolved spontaneously, the ASO was safe and well tolerated (1).

After the first dose, Susannah’s parents reported a drop in her seizures, and in the week after her 80mg dose, they reported she was having less than 30 a week, a stark difference from the sometimes hundreds a day she was having before (1). Additionally, within the first month, her gait improved, and she was now only falling a maximum of seven times a day, down from her daily fall average of 26.2 (1). Many days, her parents reported that she didn’t fall at all despite being more active (1).

“One of the biggest differences to us has been the reduction of tremors because Susannah’s improved ability to feed herself frees up precious seconds for Sally and I,” Luke Rosen said in a recent article.

Researchers also noted that her quality of speech, attention level, engagement, ability to engage in group activities, and motor function all improved. “She still can’t do math, but improved speech, better attention – to us, these are cognitive improvements,” Rosen explained.

An increase in Susannah’s quality of life score from 55.8 at baseline to 77.3 at day 308 was noted; however, unmet needs like foot pain (peripheral neuropathy), difficulty stepping, gastroesophageal reflux, and behavioral outbursts, still exist (1). Additionally, because the ASO is administered via the spinal cord, it cannot access the eye cells and optic nerve, translating to no improvement in her vision.

Susannah’s bespoke therapy helps other KAND patients

As of August 2024, Susannah had been on the ASO treatment for 20 months with a favorable safety and tolerability profile. The Nature article states that the findings support using an allele-specific ASO as a potential treatment for KAND and that they plan to treat other patients with the disease (1). However, as KAND can be caused by more than 100 different mutations in the KIF1A gene, multiple ASOs will need to be created to treat all patients.

“Because of phenotypic variability in this condition according to variant and over the lifespan, each patient will require individualized outcome measures tailored to their age, cognitive function and disease stage, including visual impairment. A future goal is to start treatment as early as possible to prevent irreversible damage,” the study states (1).

Since Susannah, two adult patients have also received the n-Lorem drug, and in March 2023, the parents of now three-year-old Sloane Hedstrom discovered that Susannah’s ASO drug would be a fit for their daughter. In May 2024, Sloane received her first dose; on August 1st, she received her third dose while also reaching the milestone of starting her first day of school.

Sloane’s mother, Megan, says they’re seeing small changes, with her therapists noting better motor control, quicker protective reactions, and increased ability to smoothly shift her center of gravity. Sloane will receive her fourth dose in October.

Antisense oligonucleotide therapies critical for gene selectivity

Susannah’s drug is not the first personalized ASO treatment to be used successfully. Previously, the treatment was used for a child with Batten disease, as well as another case of it being used and well-tolerated in a child with ataxia-telangiectasia (1).

“Allele-specific ASO gapmers can be used for allele-specific degradation of a transcript encoding a mutant protein without altering the transcript from the wild-type (WT) allele and could be a treatment approach for diseases caused by dominant negative mechanisms,” the Nature article states.

Antisense oligonucleotide treatments, like the one created for Susannah, offer a promising path for developing personalized therapies in ultrarare diseases, which, although individually rare, collectively add up to more than 263 million people needlessly suffering with no treatment options (1). However, n-Lorem and other foundations are working to change this.

The mission of N-Lorem: leave no child behind

In 2022, about two dozen patients with a range of neurological conditions received bespoke genetic drugs costing as much as $2 million per patient. N-Lorem aims to treat at least 1,000 patients with ultra-rare conditions in the next decade and fulfill its mission of leaving no child behind. So far, n-Lorem has enrolled more than 80 patients, and its waitlist includes more than 100 patients. Dr. Crooke explained that the nonprofit plans to license findings from custom medicines that may apply to more common diseases.

Susannah isn’t the first patient n-Lorem has helped. In 2017, Dr. Crooke was asked by Kelly, a parent, to create a medicine to help with her son’s seizures that were being caused by a mutation in the SCN2A gene, which plays a critical role in transmitting electrical signals in the brain. Crooke (founder of Ionis) was still the head of Ionis at the time and said the prevalence of SCN2A patients was too small to be pursued commercially. However, the idea of using Ionis’ technology to treat ultra-rare diseases stuck with him, and in 2019, he stepped down from Ionis to focus on n-Lorem.

Kelly’s son Connor became n-Lorem’s first patient. The difficulty of creating a drug that would hinder Connor’s gene mutation while leaving the healthy copy intact stretched the timeline of the drug’s development from 18 months to more than three years. But when Connor was finally given the drug, his mom cried with happiness. After two subsequent doses, Connor’s seizures were reduced, his movement and walking improved, he slept better, and his outbursts happened less.

“While we are treating one nano-rare patient at a time, what we are learning from a single patient will help entire patient communities and broaden our understanding of how a single gene mutation can cause devastating diseases. We built n-Lorem knowing that one day we might be treating thousands of nano-rare patients,” Dr. Crooke said in the press release.

N-Lorem has created 17 drugs so far, some of which have been given to patients, while others are still undergoing regulatory review. The nonprofit provides patients a free lifetime drug supply that costs around $700,000 to develop and manufacture. It has raised more than $50 million to fund medicine with its two founding partners, Ionis and Biogen, which also provide discounted or free equipment and services, allowing n-Lorem to provide free infusions to patients indefinitely, although patients are still responsible for associated medical costs.

However, the free ASOs are currently limited to only patients in North America, making it difficult for those in other geographic areas to access treatment (2).

Mila’s story: the start of bespoke, ASO treatments

Six-year-old Mila Makovec was the first person to receive a personalized ASO for her ultra-rare neurological condition, Batten disease. Dr. Timothy Yu at Boston Children’s Hospital found a splicing defect in one of her genes and theorized that an ASO similar to nusinersen (Spinraza) — an ASO developed to treat spinal muscular atrophy by changing the splicing pattern of a gene — could be used to correct her splicing defect. Within a year, Dr. Yu and his team created an effective ASO that used the same chemical backbone and route of administration as nusinersen. After confirming it was safe in rats and receiving FDA approval for an N-of-1 trial, Mila started treatment with gradual dose increases over six months.

While the drug — named Milasen — did not ultimately provide a cure, it did slow Mila’s progression of symptoms and reduced the severity and frequency of her seizures. Sadly, in 2021, 10-year-old Mila passed away. However, the development of Milasen forged a path for customizing therapies and set a precedent for FDA guidelines for N-of-1 drugs.

The future of N-of-1 drugs

Numerous foundations now exist to create and provide treatments for ultra-rare conditions, including the Valeria Association, the KCNT1 Epilepsy Foundation, Cure Rare Disease, Mila’s Miracle Foundation, and The Institute for Life Changing Medicines (ILCM). Nobel Prize winner Jennifer Doudna, known for discovering CRISPR, also wants to develop gene therapies for rare conditions. Additionally, N=1 Collaborative and 1 Mutation 1 Medicine are helping build the necessary infrastructure, tools, and processes to create pathways that will ultimately provide patients with easier access to treatments.

Susannah, Connor, and Sloane are paving the way for personalized genetic drugs. The success of Susannah’s bespoke ASO treatment demonstrates the potential of personalized medicine in treating ultra-rare diseases. While challenges remain in developing customized treatments, the progress made in these cases paves the way for further research and development. The story of Susannah’s journey from a diagnosis with no hope to receiving a personalized treatment is a reason for optimism for other families facing similar rare and untreatable conditions.

References:

1. Ziegler A, Carroll J, Bain JM, Sands TT, Fee RJ, Uher D, Kanner CH, Montes J, Glass S, Douville J, Mignon L, Gleeson JG, Crooke ST, Chung WK. Antisense oligonucleotide therapy in an individual with KIF1A-associated neurological disorder. Nat Med. 2024 Aug 9. doi: 10.1038/s41591-024-03197-y. Epub ahead of print. PMID: 39122967.
2. Schuele R, Synofzik M, Graessner H, Aartsma-Rus A. Advancing ASO therapies from development to implementation. Nat Med. 2024 Sep 13. doi: 10.1038/s41591-024-03217-x. Epub ahead of print. PMID: 39271846.

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