Designing the first-ever trial for an mRNA-based therapeutic


Professor Li-Ming Gan, Chief Scientist, CVRM

How do you design a trial to measure the effects of a completely new therapeutic modality? This was the question we had to ask ourselves when we were planning the first-ever trial to investigate the potential pharmacodynamic effects of a messenger RNA (mRNA)-based drug modality. The answer is that it’s complicated, but a worthwhile effort as we achieved two really important breakthroughs: we developed a new clinical trial model that I believe will have huge implications for future trials, and we showed for the first time that mRNA injected directly into the skin can have a pharmacodynamic effect.

In a recent publication in Nature Communications [1], we explain how we, in collaboration with Moderna, the Karolinska Institutet, and our clinical trial partners Parexel, designed and conducted the first-ever human trial using mRNA to increase local tissue levels of vascular endothelial growth factor A (VEGF-A).

Behind the research was the idea that we could use mRNA to instruct the body to make any protein, anywhere we want in the body, by injecting it at a chosen location. It is arguably much easier to make drugs that inhibit pathological processes than it is to enhance something beneficial – but we wanted to push medical research in a new direction and look at ways we could stimulate the body’s natural, endogenous regenerative processes by building new proteins.

It sounds simple conceptually, but it took a lot of meticulous planning, and some trial and error, to get it right. We had to consider every single detail, from the dosing to the endpoints and statistical analysis – nobody had ever tried to measure the effects of an mRNA therapeutic in a clinical trial before, so there were no blueprints for us to work from.  

A new type of trial for a new type of modality

We injected mRNA encoding VEGF-A, a protein known to stimulate blood vessel growth,[2],[3] into skin on the forearms of patients with type 2 diabetes. People with diabetes often have poor blood supply to the skin, which means that any wounds or ulcers they get heal very slowly and can lead to serious complications.[4],[5],[6] In theory, VEGF-A mRNA would be useful to induce healing via blood vessel growth in any tissue – including ischaemic heart disease [7],[8] – but we started with low-risk, peripheral sites on the skin, as opposed to sensitive internal organs. This meant that our trial had an acceptable level of risk, which was really important in getting approval from regulatory authorities.

We wanted to push medical research in a new direction, knowing that if our work was a success, it could pave the way for a new era in regenerative medicine.

We used minimally invasive methods – microdialysis and laser Doppler imaging – to measure changes in protein level and blood flow, respectively, in a localised area; in this case, on the forearm. Although these are not new techniques, I believe it is the first time anyone has used them in this way to measure local protein levels in a clinical trial – they are typically used for more exploratory work, without defined endpoints.

There were lots of unknown parameters that we needed to figure out before starting: we didn’t know what peak and baseline levels of VEGF-A in skin should be, how much variability there would be between patients, or what the variation in blood flow would be at different sites. We had to answer these questions with validation studies before we could move forward. Clinical trial success depends on doing this kind of groundwork upfront; and all our discovery work in the organisation, including this study, is carried out within AstraZeneca’s ‘5R framework ’.[9]

We also needed to minimise the number of people exposed to this new candidate drug, while still gathering meaningful data. Our trial cohort therefore consisted of 15 people; the work we put into standardising measurements meant we could compare multiple sites on each patient. This innovative design meant we could keep the number of patients small and still get a valid readout for the proof of mechanism (increase in protein production), pharmacokinetics (temporal changes in protein production), and proof of principle (increase in skin blood flow), as well as indicative safety and tolerability.


In designing and conducting our trial to investigate the potential pharmacodynamic effects of an mRNA-based drug modality, we – alongside our partners – are fulfilling our philosophy of following the science. By doing this, we’re turning science fiction into science fact. We look forward to using the power of our combined expertise to explore the therapeutic potential of mRNA.

[1]. Gan L, Lagerström-Fermér M, Carlsson LG et al. Intradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes. Nature Communications10, 871 (2019)

[2]. NCBI Gene report. VEGFA. Available at: Last accessed: February 2019.

[3]. Isner J. Vascular endothelial growth factor: gene therapy and therapeutic angiogenesis. Am J Cardiol 82, 63S–64S (1998).

[4]. Singh N, Armstrong D, Lipsky B. Preventing foot ulcers in patients with diabetes. JAMA 293, 217–228 (2005).

[5]. Chantelau E. Nociception at the diabetic foot, an uncharted territory. World J Diabetes 6, 391–402 (2015).

[6]. Yazdanpanah L, Nasiri M, Adarvishi S. Literature review on the management of diabetic foot ulcer. World J Diabetes 6, 37–53 (2015).

[7]. Hughes G, Annex B. Angiogenic therapy for coronary artery and peripheral arterial disease. Expert Rev Cardiovasc Ther 3, 521–535 (2005).

[8]. Zangi L, Lui KO, von Gise A et al. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nature Biotechnology 31, 898–907 (2013).

 [9]. Morgan P, et al. Impact of a five-dimensional framework on R&D productivity at AstraZeneca. Nat Rev Drug Disc 17, 167–181 (2018).