mRNA localisation: a subcellular mechanistic target to treat pathological angiogenesis.

The vascular system is comprised of an intricate network of vessels that ensure the distribution of nutrients and oxygen to all the tissues in the human body. New vessels are formed during embryonic development and also in adult individuals during processes such as wound healing. The formation of new vessels occurs principally through a tightly controlled mechanism called sprouting angiogenesis.

During this process, endothelial cells which are the main blocks composing vessels, branch from existing vasculature to form a new sprout. In particular human conditions, insufficient angiogenesis could be the cause of ischaemic tissue. On the other hand, excessive growth of blood vessels is the hallmark of impairing or even life-threatening diseases.

For example, diabetic patients tend to suffer from dysregulated angiogenesis in the back of their eyes and if left unchecked, this can lead to blindness. During cancer progression, tumours promote angiogenesis in their local environment so they can receive nutrients and oxygen for expansion, as well as find a way to spread to other parts of the body.

Although fantastic therapies that successfully halt the formation of undesirable blood vessels are now used to treat particular complications, several problems make these strategies far from perfect. For instance, particular drugs have no effects on some patients or they may even damage some other tissues due to lack of specificity. For this reason, finding new drugs that can control angiogenesis without these caveats is one of the main interests in the field of vascular medicine.

We recently found that some messenger (m)RNAs, the middlemen between genes and the proteins, are not equally distributed throughout endothelial cells when they sprout to form a new vessel. We also found that taking these mRNAs to particular regions within the cell, where they are translated into proteins, is important to help the vessel grow. Hence, we sought to study whether perturbing the localisation of mRNAs can help inhibiting angiogenesis.

For this, we are forming a strong team of researchers with distinct key skills and who will provide invaluable expertise at particular stages of the project. We plan to use molecules complementary to sequences in the mRNAs to inhibit their transport towards the correct location. We will firstly examine which molecules can achieve this goal in the most effective way.

Afterwards we will use a collection of assays that simulate early stages of angiogenesis in a petri dish, to understand how these molecules inhibit endothelial cell sprouting and vessel formation. Next, we will transfer what we learned to mouse models to investigate the therapeutic potential of these molecules. Our experiments will be focused on a very well understood network of vessels found in the back of the eye.

We will study how the disruption of mRNA localisation halts dysregulated angiogenesis, ensuring minimal animal usage and suffering. Altogether, we hope that our highly novel approach will lead to the development of new drugs, which could help circumvent current setbacks in the treatments of angiogenesis-related complications. Importantly, our work will also open new doors for the development of drugs to target localised mRNAs in a wide range of human diseases.