NEW YORK – UK startup SynaptixBio has ambitions to enter the antisense oligonucleotide (ASO) space by developing treatments for rare leukodystrophies.
The company's first ASO therapy program is focusing on hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), a rare leukodystrophy. Leukodystrophies are a group of disorders that affect the myelin sheaths that insulate neurons within the white matter of the brain. The US National Institutes of Health estimates that fewer than 1,000 people there have been diagnosed with H-ABC.
The company has also begun preclinical work on an ASO therapy for a second rare leukodystrophy indication, called isolated hypomyelination.
Oxford-based SynaptixBio is a "virtual company" focused solely on rare leukodystrophies for the foreseeable future, according to CEO and Cofounder Dan Williams. There are currently around five employees, mainly scientists and one physician, who manage investments and scientific programs. The firm recently renewed an agreement with contract development and manufacturing organization Evotec to carry out all necessary lab work and advise on experimental designs.
"This allows us to keep our overhead very low," Williams said. "We can channel investors' funds straight into the research, instead of having to pay for offices, labs, et cetera."
Although the company has yet to finalize which H-ABC therapeutic candidate it will put forward, it is already discussing clinical trial designs with the US Food and Drug Administration and the UK Medicines and Healthcare Products Regulatory Agency. Last year, the company won a £490,000 ($628,650) BioMedical Catalyst grant from Innovate UK to further develop its ASO-based leukodystrophy therapies.
"The main markets that we're going to target will be Europe and the US," Williams said, adding that the firm's long-term growth plans may include "potential markets" in China and India.
SynaptixBio acquired the license to a methodology patent covering therapies relating to the TUBB4A gene, which is altered in some leukodystrophies such as H-ABC, as well as to a candidate ASO, in 2022 from the lab of Adeline Vanderver, program director of the Leukodystrophy Center at Children's Hospital of Philadelphia. Vanderver is now part of SynaptixBio's scientific advisory board.
While that particular candidate ASO proved ineffective, the company is working with Evotec to develop new ones based on the patented methodology it acquired from CHOP. SynaptixBio will retain all intellectual property related to those candidates.
The new ASOs that SynaptixBio is developing target a mutated form of the TUBB4A gene, which codes for a type of tubulin –– building blocks of the cytoskeleton –– found in oligodendrocytes in the brain. The mutations that cause H-ABC result in a toxic form of tubulin that disrupts microtubule formation in oligodendrocytes. Without a fully functioning cytoskeleton, myelin fails to form around those cells, disrupting nerve signal transmission and leading to H-ABC's symptoms, such as impaired movement, speech, and mental and physical development.
Williams explained that oligodendrocytes use multiple types of tubulin in constructing their cytoskeletons. "They can substitute [those] in to replace the one we're knocking out," he said.
In designing ASO therapies for rare diseases, SynaptixBio is entering a vibrant market space. Ionis Pharmaceuticals, for instance, is preparing to launch a pivotal trial next year for its candidate ASO therapy for Angelman syndrome, and recently won priority review for another ASO, this one targeting familial chylomicronemia syndrome.
Last month, QurAlis granted Eli Lilly exclusive global rights to develop and commercialize its ASO therapy for amyotrophic lateral sclerosis and frontotemporal dementia, as well as other neurodegenerative diseases.
"ASOs are ideal for genetic diseases because [they] can be designed to address the cause of the disease," said Stan Crooke, founder, CEO, and chair of the N-Lorem Foundation, a nonprofit that researches and develops ASO treatments for ultra-rare diseases. "[ASOs] are just a [much] more efficient technology than traditional small molecules or monoclonal antibodies."
Crooke noted that ASOs –– and RNA-targeted drug discovery in general –– have been enjoying a "groundswell of interest" for several years. Another factor in their favor, he said, is that although these are gene-targeted therapies, they are akin to traditional small molecule therapies in that they only persist in the body for relatively brief periods of time, as opposed to gene therapies that make permanent changes to a patient's DNA.
This, Crooke said, helps ease their path to clinical trials relative to gene therapies. "We have a lot to learn before we know how to use [gene therapy] safely," Crooke said, whereas "almost every major company and many biotech companies have RNA-targeted drug discovery programs."
In its bid to develop ASO therapies, SynaptixBio has so far raised £2 million in a seed funding round last year and an additional £11 million since then. The company seeks to raise an additional £15 million, which Williams said will take SynaptixBio through its planned clinical trial program slated to begin early next year.
"Costs are this high as the trial is very complex as a [central nervous system] pediatric study [taking place] over at least two regions, the UK and US, in a rare disease that is likely to encounter issues recruiting patients," he said.
In the coming months, the company hopes to finalize its choice of candidate therapy and initiate manufacturing and toxicology studies. Williams said the firm has several contract manufacturing and research organizations shortlisted to conduct these studies, though SynaptixBio will also keep working with Evotec.
"We're moving quite rapidly toward selecting a development candidate," he added. "Hopefully, we'll get it into the clinic very quickly after that."