Using local cytokine delivery to prevent lung pathology

We have an exciting new story out at Science Immunology! It uses AAV-mediated cytokine delivery to change the lung environment. We can boost lung Tregs or deliver anti-inflammatory cytokines, preventing fatal respiratory collapse.

This story started during the COVID pandemic. Our first Cambridge PhD students joined during lockdown, and a talented student, Ntombizodwa Makuyana (now Dr Ntombizodwa Gentry), wanted to work on a potential therapeutic.

James and I had only just moved to Cambridge, and we still had a team in Belgium. They were processing clinical samples from COVID patients, so we already had a good idea that the respiratory failure was driven by excessive inflammation.

At the time we had been working on a system to boost Tregs in the brain. Our AAV system was working great, so we thought "what if we tried to do the same thing in the lung?" It took quite some trial and error, but eventually we found that intranasal delivery of AAV6.2 with the CC10 promoter limited expression of our cargo limited to the lung.

The system works great! AAV6.2.CC10 driving IL2 production gives an expansion of lung Tregs without impacting other sites, even the draining LN of the lung. And it is not just IL2 - in the same way we can drive IL10 or IL1RA in the lung without altering systemic levels. Pick your own cargo!

We never ended up testing it in SARS-CoV2 infection - by that point the vaccine had come along. But COVID isn't the only important lung infection. You might not even have heard of one of the most deadly: Influenza-Associated Pulmonary Aspergillosis (IAPA).

Aspergillus is a fungus common in decaying soil, that can infect the lung. For healthy individuals it is rarely a problem, and is easily cleared. But Aspergillus is a hidden killer. The Joost Wauters, Greetje Vande Velde and Stephanie Humblet-Baron teams teams had found that coinfection of influenza and aspergillus is extremely deadly, with an ICU mortality rate of >50%, and lethal coinfection in mice.

So James, Oliver and Milla headed over to Belgium and teamed up with Laura Seldeslachts and Lauren Michiels to test our AAV-cytokine delivery approach in coinfected mice. Success! In every measure we tested, our treatment reduced severity from fatal respiratory failure down close to a regular flu infection.

The best part is, because we only altered lung immunology, the anti-viral responses from the LN were intact, so we could reduce lung inflammation without giving the infection a free-pass. This is why tissue immunology has such potential - only hit the site needed!

Thanks to the ERC, Wellcome Trust and FWO for funding. 

Read the full story here