Elucidating the role of ATP13A3 in Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension (PAH) is a progressive and lifethreatening

condition with a poor survival due to the lack of an

adequate cure. This highlights an unmet need for new therapeutic

strategies for PAH treatment. Recently, a genetic screen on a cohort

of PAH patients revealed pathological and dominant mutations in an

uncharacterised gene, ATP13A3. ATP13A3 is closely related to

ATP13A2, and the host lab proved that ATP13A2 is a polyamine

transporter. Polyamines are vital molecules for the cell and

polyamine dysregulation is implicated in various diseases. Based on

strong preliminary data, we hypothesize that ATP13A3 is also a

polyamine transporter. Dominant PAH mutations may increase

polyamine transport and uptake in cells, causing toxic accumulation

of polyamines in the cell. To test this hypothesis and validate

ATP13A3 as a drug target, we would like to (i) establish that

ATP13A3 is a polyamine transporter, (ii) study the effect of PAH

mutants on polyamine homeostasis; and (iii) elucidate the ATP13A3-

dependent PAH disease mechanism in cellular models and

determine if the disease-phenotype is reversed upon ATP13A3

inhibition. Towards a drug screening program to identify ATP13A3

inhibitors, we will optimize assays for high throughput screening with

the Centre for Drug Design and Discovery. The role of ATP13A3 in

more advanced PAH models will be explored in collaboration with Dr.

N. Morrell at the University of Cambridge.