Inside SynaptixBio's Mission To Develop A Therapy For H-ABC

By Erin Harris, Editor-In-Chief, Cell & Gene
Follow Me On Twitter @ErinHarris_1

Rare Disease Day was observed on February 28th, but for the families living with these conditions, and the scientists working to treat them, the reality is that rare disease awareness is every day. I caught up with Dr. Dan Williams, CEO of SynaptixBio, a company focused on some of the most devastating and least understood neurological conditions, including the ultra-rare leukodystrophy H-ABC. With only tiny patient populations and limited clinical data, developing therapies for diseases like these presents enormous scientific, regulatory, and economic challenges. Dr. Williams joins me to discuss how SynaptixBio is advancing an antisense oligonucleotide therapy designed to silence the mutant TUBB4A gene, what it takes to move an ultra-rare disease program toward the clinic, and why close collaboration with families and patient communities is essential to making progress.

SynaptixBio is focused on ultra‑rare leukodystrophies such as H‑ABC, where patient numbers are tiny and progression is devastating. From your perspective, what are the most unique challenges that rare disease biotechs face when trying to move a therapy from concept into first‑in‑human trials, compared with more common indications?

Dr. Williams: Rare diseases represent a major challenge for healthcare systems, drug developers, and governments worldwide. Their low prevalence makes rare diseases challenging to diagnose, treat, and research due to limited patient data and clinical expertise.

A significant challenge in the road to curing rare diseases is the cost, which is typically much higher than creating drugs for less common disorders. The pool of patients able to take part in clinical trials is small, as is the market.

Historically, major pharmaceutical companies have shied away from researching rare diseases primarily because they were not considered commercially viable, as small patient populations meant low returns on investment compared to blockbuster drugs for common conditions. While the effects of rare diseases on families are no less tragic than those of more common disorders, big pharma does not deal in emotions and tends to invest in research with more economic incentives.

That means smaller biotechs are more commonly involved in the research of rare diseases, but of course they deal with more stringent budgets. Although this trend has begun to shift in recent years, largely due to regulatory incentives, rare diseases are still ‘rarely’ a priority for those larger pharmaceutical companies.

Even when the funding is available, data is scarce and fragmented. Sufficient data is needed for meaningful analysis, but patients are often spread across the world, many likely unaware they even have a rare disease. The data that is recorded can be siloed across hospitals, research centres and pharmaceutical companies, making collaboration a laborious task.

You’re building your platform around antisense oligonucleotide gene silencing rather than classical gene replacement. Please explain in practical terms how your ASO works at the RNA level.

Dr. Williams: The human genome contains around 20,000 protein encoding genes, each a template for a protein that plays a role in the body’s structure, function and regulation. A small percentage of gene variants, whether hereditary or non-inherited, trigger the production of disease-causing faulty proteins, leading to disease.

Diseases caused by changes in proteins range from mild to severe, and include rare diseases, cardiovascular disease, cancer, and other disorders. Treatment approaches for genetic diseases have focused on managing symptoms through small molecules and biologic therapeutics. Newer approaches target the genetic mutations themselves, by replacing (gene therapy), removing (gene editing) or muting (gene silencing) the genetic code.

The gene silencing approach works by targeting mutations and preventing or reducing the expression of associated disease-causing proteins. The best-known gene silencing technology is antisense oligonucleotides (ASOs), which are single or double stranded synthetic strings of nucleotides that bind to messenger RNA and effectively stop the production of the associated toxic protein. With the toxic protein suppressed, other proteins can step in to do the job.

Research into ASOs is thriving, particularly for the treatment of rare genetic disorders, neurological diseases, and cancer. Around 80% of all rare diseases are monogenic, meaning they are caused by mutations in a single gene, making them ideal targets for gene silencing approaches. SynaptixBio has selected its lead candidate ASO to treat H-ABC and is hoping to enter clinical trials early in 2027.

SynaptixBio’s TUBB4A antisense oligonucleotide, SB-19642, is a DNA molecule with RNA ‘wings’ that binds to the mRNA. It is highly specific, targeting only the aberrant tubulin, allowing the other tubulins to continue to play their physiological roles.

As you move an antisense therapy for a pediatric leukodystrophy toward the clinic, what have you found most critical in trial design and operational planning that other CGT biotechs should be building in from day one to avoid delays and failed studies?

Dr. Williams: I am not a clinician and not the person pulling together the trial design or clinical operations. However, in overseeing this I can say the following: All the above are equally required to take a molecule through to the clinic. Planning and getting endpoints correct are obviously required to measure improvements; however, these need to be validated and the best way to do this is through family engagement.

Trial size is going to be small and thus powering the trials statistically will be difficult. Regulators will ask for placebos and control the trials. These are often not acceptable to families for their children. As a result the natural history data is important to serve as an external control; however, these need to be to the standard that is accepted by the regulatory agency – often very expensive non-invasive studies need to be performed.

Additionally, biomarker assays and their validation need to be thought out and validated often in collaboration with regulatory bodies. CMC needs to be planned to fit the the trial and trial timetable.

While it is not possible to predict everything it is important to engage with regulatory bodies and discuss your plans as early as possible.

SynaptixBio’s lead ASO, SB H‑19642, is designed to silence the mutant TUBB4A gene and reduce production of toxic proteins. Based on what you have seen so far preclinically, what are your hopes for what this therapy could change in the lives of children with H‑ABC; are we talking about halting progression, improving function, or possibly even reversing some aspects of the disease?

Dr. Williams: It’s always difficult to say until we get into the clinic. However, mouse models suggest that if treated early enough we are able to see motor improvements in the animals with mutations. We also see a threefold increase in survival.

The brain is an amazing thing and adapts and heals extremely quickly. It is possible that silencing TUBB4A may enable remyelination in patients (as seen in diseased mice) and the brain will then adapt to enable improvements in areas affected by the disease.

Any improvement in quality of life would be good in this unmet disease population and this may involve halting progression; however, the therapy may improve function and reverse some aspects of the disease – this will remain unknown until we get the molecule into the clinic.

Most H‑ABC patients are babies or young children whose families suddenly find themselves navigating feeding issues, mobility loss, communication challenges, and an uncertain prognosis. How do those day‑to‑day realities for families shape the way you design your trials, communicate risk and expectation?

Dr. Williams: Again, I am not the clinician or in clinical operations. However, these factors are all considered. As there is currently no treatment for the children with the disease beyond treating the symptoms (i.e. physiotherapy) the families welcome any treatment that can improve both their QOL as well as the child’s. We engage with the families, both here and in the US, to help define the endpoint and clinical assessment we need to show benefit as the families know what they can monitor and what to best expect form the treatment. 

For CGT teams that are also working in ultra‑rare indications, what are one or two concrete lessons from SynaptixBio’s H‑ABC program that you think are most transferable to other small patient population gene silencing or gene therapy programs?

Dr. Williams: Even though the trials may be short they will be expensive (from preclinical through to registration) and the risk benefit is often not looked at in enough detail by investors. This result is funding being difficult to gain

Keep plugging away with everything as the rewards from this are so great and the work is so important (and I don’t mean financial reward). Work very closely with the families and parent associations from the very beginning as they know the patients better than anyone and they motivate you to keep going.