SynaptixBio Ltd.

As we approach the end of 2024, we have been reflecting on another busy year for the team at SynaptixBio.   Firstly, and most importantly, we welcomed three amazing new team members - Uwe Meya joined as Chief Medical Officer, David Rigby as interim Head of Research and preclinical Development, and Tracy Matthews as Executive Associate. All have made an immediate and hugely positive impact.   Uwe has made real progress with clinical development, and we are rapidly narrowing our range of candidate drugs to tackle H-ABC, a rare, deadly, and currently incurable disease that affects mainly babies and young children, with a view to entering the clinic in 2025.   In support of this, we were awarded a £2million Biomedical Catalyst grant from Innovate UK – to whom we are extremely grateful.   So it is with excitement and anticipation that we look ahead to 2025 and the next big steps towards tackling this debilitating neurodegenerative disease.   With that we wish you the warmest season’s greetings, and health and happiness for the New Year.

ANNOUNCEMENT: This is the 5th in our series of posts about rare diseases; here we discuss the issues and complexities around orphan drugs.   What are orphan drugs and what rules apply to them?   Orphan drugs are medicines used to treat rare diseases. By definition there is a limited market for such drugs, which led the US government in 1983 to pass the landmark Orphan Drug Act (ODA), specifically to incentivise drug development by pharmaceutical companies.   These incentives included things like tax relief/credits, a period of market exclusivity, and reduced regulatory fees.   Many other countries now have similar programmes, though rules and incentives vary.   In the UK, applications for a drug to be given orphan status are made to the Medicines and Healthcare products Regulatory Agency (MHRA).   The equivalent body in the EU is the European Medicines Agency (EMA), and in the US it is the Food and Drug Administration (FDA). Strict criteria apply for drugs to be granted orphan status; for example, they must target life-threatening or severely debilitating conditions, and there must be no existing treatment method.   The global market for orphan drugs is growing fast; according to one report (from global business intelligence platform Statista) it was worth $185 billion in 2024, and will grow to $271 billion by 2028.    The term "orphan” was first used (in relation to drugs and diseases) in an article from 1968, where a paediatrician argued that children were becoming "therapeutic or pharmaceutical orphans", because few drug developers studied the impact of drugs in children and that most drugs contained disclaimers stating that the drugs should not be used in children.   A fuller history of the origin and subsequent application of the term can be found by following the link below.

ANNOUNCEMENT: This is the fourth post in our series about rare diseases. Here, we consider the nature and impacts of TUBB4A leukodystrophies.   There are over 100 different types of leukodystrophy, with TUBB4A-related conditions comprising around 9% of these. The most common, and most severe, variant of TUBB4A-related leukodystrophy is H-ABC, which results in less than normal amounts of myelin being deposited on the nerve fibres in the brain, impacting the effectiveness of the signals that pass along those fibres.   The impacts of this single-gene mutation are devastating, affecting every aspect of normal life:   - Cognitive ability (reasoning, thinking and remembering) - Feeding and digestion (swallowing, colic, regurgitation, constipation) - Mobility (coordination, balance and walking, sometimes total loss of mobility. Infants may be unable to sit up or control head movements) - Hearing - Vision   Of course, not everyone who’s affected will suffer from all of these, and severity can vary widely, but this is a very serious, indeed life-limiting condition.   Early diagnosis is vital to give families the best chance of finding the right help and support, so we continue to push for wider genetic testing at birth.

ANNOUNCEMENT – This is the second part of the third post in our series about rare diseases. In part 1 we discussed gene silencing in general; here, we discuss one form (antisense oligonucleotides) that’s proving increasingly interesting as a potential therapy for a wide range of neurodegenerative disorders. So, to start, nucleotides are molecules that form the basic structure of DNA and RNA. Oligo is from the Greek and means ‘just a few’. So oligonucleotides are short pieces of modified DNA, typically comprising around 20 nucleotides. mRNA is a copy of DNA that travels from the nucleus to another part of the cell where proteins are made. It is the ‘sense’ part of mRNA that results in a protein. Antisense oligonucleotides (ASOs) are called antisense because they bind to the sense part of mRNA, in a complementary manner, preventing it from producing its associated protein.   ASOs are currently in trials for Alzheimer’s disease (University College London Hospital), where they have already demonstrated promising results, and are being investigated as potential therapies for Parkinson’s and Motor Neuron Disease. We are determined to get to clinical trials as soon as possible with our candidate ASO for treating H-ABC.

Wonderful to see Amy Sheridan-Hill featured in the Daily Mirror talking about her hopes for a drug that could help treat her son Frankie's rare, life-limiting and currently incurable condition - H-ABC. Amy is co-founder of the H-abc Foundation UK, which raises awareness and money to help fund the search for a therapy. We are doing everything possible to get to the start of clinical trials of our candidate drug, though we can't say exactly when that will be. Huge thanks to Saskia Rowlands for researching, interviewing and writing this story.

ANNOUNCEMENT: This is the third in our series of posts about rare diseases; here we discuss the mechanisms and benefits of gene silencing, before discussing one form that’s proving to be applicable to a wide range of neurodegenerative conditions – antisense oligonucleotides (ASOs). What is gene silencing – and how does an antisense oligonucleotide work? This is a complex subject, so we will split it into two parts (and posts). PART ONE, below, is about controlling gene expression. PART TWO, available in a week or so, will discuss antisense oligonucleotides. So, firstly, a little cell biology. Genes are sections of DNA, which is contained in the nucleus of the cell. Each gene contains the code for creating a specific protein. The DNA code for the protein remains in the nucleus of the cell, but a copy of it, called messenger RNA (mRNA), moves from the nucleus to another part of the cell where it is used to make proteins. Gene Silencing Gene silencing simply means suppressing the expression of a specific gene, preventing it from producing its associated protein. Critically, the underlying DNA is unaltered. Synthetic gene silencing molecules mimic the body’s natural RNA interference (RNAi) process, which is part of the immune response system. In the natural RNAi process, RNA molecules attack viruses, bacteria and parasites – as well as correcting mutations. Although they are involved in the production of new proteins, these RNA molecules can also work in reverse, moderating or adjusting the activity of genes.   Gene Editing Gene editing involves making changes to the actual DNA sequence. The DNA is cut at a specific location, after which the cell’s natural repair mechanisms either correct or alter the genetic code. Unlike gene silencing, gene editing is a permanent modification – it will be inherited.   Benefits of Gene Silencing Reversibility: Since gene silencing does not alter the underlying DNA sequence, its effects are generally reversible. This is vital in cases where permanent changes could introduce risk. Targeting: Many diseases, including cancer, are caused by the overproduction of specific proteins. Gene silencing can target the genes that make those proteins. Precision: RNA interference can target very specific genes. This minimises side effects. TUBB4A leukodystrophy is caused by a mutation in a single gene, which can be targeted specifically using a form of gene silencing technology called antisense oligonucleotides – but more about those in the next post.

Fantastic news this morning that NHS England has introduced genetic screening for over 200 rare diseases. This will help many patients and families; rare diseases are very often life-limiting. We hope it can be extended more widely to include those rare diseases for which there is currently no treatment – early diagnosis can avoid years of uncertainty, and allow families to gain better access to care and support services.

ANNOUNCEMENT: This is the second in a series of posts about rare diseases; here we focus specifically on TUBB4A-related leukodystrophy. What exactly is TUBB4A-related leukodystrophy?   Firstly, a leukodystrophy is a disease of the white matter in the brain and spinal cord (the word comes from the Greek leuko - meaning white, dys – meaning abnormal, and trophos – meaning growth).   Leukodystrophies (52 have been identified so far) affect the myelin sheath, which insulates nerve cells in the brain (neurons) and allows messages to be transmitted between them (along nerve fibres).   TUBB4A stands for tubulin beta – 4a, a gene that contains instructions for making the protein beta-tubulin, which is found primarily in the basal ganglia and cerebellum, structures in the brain that are closely associated with movement.   A mutation in the TUBB4A gene is, predominantly, random. It can cause a range of conditions (TUBB4A-related leukodystrophies) from the most common and severe (H-ABC) to the rarer and milder (Isolated Hypomyelination).   Hypo is also from the Greek and means less, or below normal - so hypomyelination (the ‘H’ in H-ABC) means below normal levels of myelin sheath. ABC is Atrophy of the Basal ganglia and Cerebellum.   Isolated Hypomyelination is effectively H-ABC without the ABC. We are working on a potential therapy for H-ABC, with the aim of entering clinical trials as soon as possible.

ANNOUNCEMENT: Over the next few weeks we will be posting on a range of topics around rare diseases - their causes, nature, impacts and treatments. The first post (below) is about the number and nature of rare diseases. The full list of topics we will post about is:   - Rare diseases – not a numbers game - What exactly is TUBB4A leukodystrophy? - What is gene silencing – and how does an antisense oligonucleotide work? - The nature and impacts of TUBB4A leukodystrophies - What are orphan drugs and what rules apply to them? - How are clinical trials organised and run? Rare Diseases – not a numbers game*   TUBB4A leukodystrophy is just one of a large and increasing number of recognised rare diseases.   Estimates vary, but the general consensus is that there are somewhere between 6,000 and 10,000 worldwide.   Definitions vary too:   United States: 1 in less than 200,000 people European Union (including UK): 1 in less than 2,000 people.  Japan: 1 per 2,500 people. World Health Organization: 65 per 100,000 people.    However they are defined and counted, we can all agree they affect a small number of people - but because there are so many, today approximately 300 million people worldwide live with a rare disease.   What are the defining characteristics of rare diseases?   Around 80% of have a genetic cause, and almost 70% of those develop symptoms in childhood.   Sadly, given their generally life-limiting impact, only about 5% have approved treatments; equally sad is that the average time for an accurate diagnosis is 4-8 years.   Tragically, 30% of children with a rare disease die before age 5 years.   This is why we do what we do. *The figures quoted are from several sources: WHO/Orphanet, NORD and The Lancet, though multiple sources use figures in that range.

lecanemab has recently been approved for use in the UK as a treatment for Alzheimer’s. This type of drug reduces amyloid protein lesions on the brain.   The Alzheimer’s therapy trial underway at University College London Hospitals NHS Foundation Trust uses a form of gene silencing to stop production of the Tau protein, which gets inside the brain’s nerve cells (neurons) – effectively clogging them up.   Amyloid and Tau are the two dominant proteins prevalent in people with Alzheimer’s.   The technology we are using to tackle H-ABC, a rare, deadly and currently incurable neurodegenerative disease, uses another form of gene silencing.   It’s wonderful news that there are so many initiatives underway to tackle these central nervous system diseases.