Kinds of KANDness: Battling nano-rare disease with oligos
A lone protein seems to “walk” hand-over-hand along a bumpy green road. Trailing behind, an almost gelatinous blue ball follows in tow. It’s an image made famous by the 2006 video “The Inner Life of the Cell” from BioVisions at Harvard University, and now, these “motor proteins” are the focus of therapeutic development for rare disease.
There are a few ways for cellular machinery to get around the cell, including by vesicles or simple diffusion. However, larger cargo often needs to be pulled through the cells along something resembling a molecular “highway” – a network of structures called the cytoskeleton. The nano machines responsible for processively hauling organelles, and other components across the cytoskeleton are called kinesins.
The picture is more complex than the one presented in BioVisions, but the point is clear: without kinesins, the cell’s basic functions are severely disrupted.
The crucial role these proteins play in cellular function means that variants in kinesin genes can lead to devastating effects. Take KAND (KIF1A-associated neurological disorder), a fatal degenerative condition caused by variants in the kinesin KIF1A and characterized by cognitive degeneration and loss of motor skills. Early diagnosis and intervention are key to improving quality of life and – potentially – survival.
The problem with conditions like KAND is that they are so uncommon that they only impact a few people worldwide. This reality clashes commercial viability, leaving patients adrift.
A recent Nature Medicine n-of-1 case study from researchers based at Columbia University, Harvard University, and other institutions demonstrates that a bespoke ASO treatment may be a viable method for treating KAND. Their approach provides evidence for the viability not only of ASO therapies, but of nonprofit models of clinical development.
Spoiling the rotten apple
KAND is a unique degenerative condition that doesn’t have a defined symptomatic profile. Presentations can include vision loss, variable pain sensitivity, intellectual disability, spastic movement, and epilepsy. Severe cases can even lead to death in infancy. Just as varied are the limited treatment options: some patients receive antiseizure medications, while others may use baclofen and Botox to manage involuntary movement.
In their study, corresponding author Wendy Chung and her team have developed the first ever KIF1A-targeted therapy. They designed an ASO specifically to target and silence the pathogenic version of KIF1A – leaving the healthy wild-type copy of the gene intact. They delivered their new drug to their nine-year-old patient, Susannah, who has a heterozygous missense variant in KIF1A and has been in Chung’s care for around eight years.
The authors first showed that, in vitro, the ASO was able to specifically reduce the levels of the harmful copy of KIF1A. They measured the expression of both wild-type and pathogenic KIF1A mRNA in induced pluripotent stem cell-derived neurons and, after administering their ASO, saw a significant drop in the missense variant version of KIF1A.
Chung and colleagues then administered their ASO to the patient intrathecally. This process involves an injection into the spinal canal with the goal of allowing the drug to directly enter the cerebrospinal fluid and bypass the blood-brain barrier (BBB). Once inside, the ASO can go after the harmful KIF1A transcript and, hopefully, provide relief.
Eschewing complications, providing relief
The ASO approach taken in this case study is not without its limitations. The authors note that the drug is unable to address some symptoms, such as optic nerve atrophy, due to how the treatment is administered. Without delivering directly to the eye, these KAND manifestations are unlikely to improve.
Furthermore, there was at least one complication during treatment where the intrathecal injection led to a collection of cerebrospinal fluid in the patient. This event was severe and painful enough to render Susannah unable to walk for a week, although the situation ultimately resolved spontaneously.
As we have previously reported, alternative delivery approaches are hoping to eschew this more invasive delivery approach. “Other methods could provide advantages,” Chung told Tides Global. “I hope the current ASO is a bridge to a better treatment in the future.”
Thankfully, this initial complication was, ultimately, not representative of the remainder of the study. Chung and co-authors found that the ASO treatment itself was in fact well-tolerated with minimal side effects.
This gave the treatment room to prove its efficacy. In their report, Chung and the team showed that the frequency of harmful events like falls or behavioral arrest were reduced over the nine months the patient was monitored. Moreover, cognitive ability remained stable throughout the trial while overall quality of life improved.
For some patients, even a modicum of relief is cause for excitement. As one KAND parent put it: “I’ve come to terms that she will never walk/stand. But for her to see the beauty surrounding her, even the simple things like watching a movie – I'd love for her see my face smiling back at her.”
Questions remain as to whether this treatment will alleviate other symptoms of KAND. This includes gastroesophageal reflux and foot pain, neither of which were reduced following treatment. The value of a study of a single case study is also limited; further investigation with more patients could help extend this approach to other cases of this disease.
Still, any improvement in this degenerative illness is a significant step forward, and this case study clearly shows the effectiveness of specifically targeting pathogenic alleles in patients. Chung even emphasizes that the lessons learned in this pilot can extend to other rare genetic disorders.
Dylan Verden, Chief Science Officer at the nonprofit organization KIF1A.org, agrees. “We’ve been talking about ASOs and Susannah’s journey for years, and always with the qualifier that nothing had been published yet,” he told Tides Global. “To have this tangible case study, some proof in the pudding that these treatments can make a difference, has been incredibly exciting for the community.”
Bringing nano-rare diseases into the spotlight
This case study emerged out of a program initiated by the n-Lorem Foundation, a nonprofit which focuses on ASO-based treatments for nano-rare (1–30 patients worldwide) diseases. The organization exists because the commercial viability of rare – much less nano-rare – diseases is practically nonexistent, leaving patients without recourse.
This case study is the first example from the organization demonstrating the effectiveness of their approach.
For researchers like Chung, there is also an element of personal investment. “As a physician who cares for many patients with rare genetic diseases, I strive to correctly diagnose patients and find treatments for them,” she said. “These nano-rare diseases are too rare to care for many others, so I try to step in and fill that gap.”
Major research institutions are also getting onboard with this method. Great Ormond Street Hospital (GOSH) in London has announced plans to acquire the license for the gene therapies it develops to combat rare disease. The GOSH website suggests that this will mean “patients can directly access and benefit from the treatment.”
Their reasoning is much the same as n-Lorem Foundation: ultra-rare diseases just aren’t profitable, leaving patients like seven-year-old Sarah – who has the ultra-rare condition ADA-Severe Compromised Immuno-deficiency (ADA-SCID) – without options.
“For rare and ultra-rare diseases, it’s a sad fact that there is little commercial reason for companies to develop costly treatments with very small markets,” says Claire Booth, professor at GOSH and Great Ormond Street Institute of Child Health. “This means that treatments that have been shown to work through research are not getting to patients who could benefit from them.”
Drugs like those proffered by the n-Lorem Foundation and GOSH are an exciting route forward for those suffering from extremely uncommon illnesses. Yet the need for these organizations also highlights those who get left behind by industry.
For Chung, there’s a long-term strategy in treating rare diseases like KAND. “When many mutations in KIF1A can be treated with a single or small number of reagents or if the cost of development/testing is driven down, it may be more commercializable,” she said. “My ultimate goal is to scale treatment of rare genetic diseases.”
It’s a steep hill to climb, but Chung isn’t daunted. “This isn’t easy and it’s important,” she observed. “Rare diseases are individually rare, but collectively common.”
This case study already portends further developments for KAND treatment. Verden says that the ASO used for Susannah’s case was “designed for equity” – so it should work for patients with other KIF1A variants, as well.
“It’s important to remember that this case study was a snapshot of Susannah’s first year of a lifelong treatment; in the meantime, she’s still paving the way for others,” he said. “In fact, a second pioneer, Sloane, has also begun dosing, and we have been talking with other families who are interested in pursuing these routes.”
Verden stressed how significant this paper is for patients and their families. “Given that we’ve been on this trek for so long, I think this study felt like a sign in the wilderness saying, ‘there is a path here, keep going.’”
