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How our technology works

Exploiting the alternative splicing of vascular endothelial growth factor (VEGF)

Exonate’s science targets mRNA altering it so that an isoform of VEGF (165b) is produced to cause inhibition of new blood vessel growth.

  • DNA

    What does it take to make a human? On a genetic level, the answer is deoxyribonucleic acid – or DNA as you might know it. DNA is a double stranded molecule that tells all the cells in the body how to build all the components you need to live. To contain all this information, DNA is an extraordinarily long molecule – in the cell it is super coiled and compacted, but if you stretched out the DNA from a single cell, it would be about 2 metres long. But what exactly is in this enormous molecule?

  • Genomics

    The DNA in humans is made up of around 20,000 genes known as the genome. Genes alone, however, are not enough – the functions of the body are actually performed by proteins, which are created from the instructions in the DNA. The DNA is first copied into a single stranded form, mRNA, which is then used as a template for the construction of proteins by other cellular components. Think of DNA as a recipe book, mRNA as a photocopy of one of the pages and the protein as the final cake you bake using the copy of the instructions.

  • Proteome

    This complex process allows us to create almost 1,000,000 proteins. The proteome is the entire set of proteins expressed by a genome. But how can 20,000 genes result in fifty times as many protein products? Surely 20,000 recipes lead to 20,000 products? This is where alternative splicing comes in. Initially observed in 1977, alternative splicing allows alterations to the mRNA before it is used to make proteins in order to produce a different product. Pre-mRNA is made of coding regions called exons and non-coding regions called introns. Exons may be included or excluded to create a new protein with a different function to the original. Using our baking analogy, this is the equivalent of adding a flavouring, or changing the flour used to make it gluten free.

    With 95% of the human genome known to be alternatively spliced, this is a huge area of research. Given that a change in splicing can result in proteins with different functions, it is unsurprising that abnormal splicing is implicated with disease. We frequently talk about upregulation of a certain gene and how we can target this therapeutically, but sometimes this upregulation is not just a result of how a gene is expressed, but how it is being spliced.

  • SRPK1

    The protein that controls which type of VEGF is produced is an enzyme, SRPK1. Inhibition of SRPK1 with our small molecule inhibitors results in a reduction of VEGF-Axxxa isoforms which are commonly high in wAMD, and increases VEGF-Axxxb isoforms which leads to a reduction in vessel growth in the back of the eye, and ultimately, the prevention of vision loss. VEGF-Axxxb isoforms have also been shown to protect cells in the retina from the damage and death commonly seen in wAMD which can lead to geographic atrophy and promotion of angiogenesis, suggesting that our compounds may have an additional mechanism of action over currently available therapies.

  • Innovation

    Current therapies already involve the inhibition of VEGF-A, but these therapies target all isoforms of VEGF-A regardless of whether they are pro- or anti- angiogenic, and also require injection directly into the eye. Our novel compounds not only increase the ratio of anti- to pro- angiogenic VEGF-A isoforms, they are designed to be delivered as an eye drop rather than as an injection.

    Using our innovative technologies, we aim to develop a minimally invasive therapy to prevent vision loss in patients with DME and wAMD.