Description of proposed project

Lung disease is the third leading cause of death worldwide. Here, I propose to treat lung disease using inhaled lipid nanoparticles (LNPs) to deliver messenger RNA (mRNA) directly to the lung. This is the same core technology behind the Pfizer-BioNTech and Moderna COVID vaccines, but chemically tuned for lung delivery, one of the hardest problems in gene therapy. Previously, I published the first study showing broad mRNA delivery to ferret lungs throughout the airway tree; this is a key milestone since ferrets are anatomically and physiologically far closer to humans than mice are. For this reason, ferrets are the industry standard for preclinical inhaled gene therapy testing.

More recently, I developed a new mRNA cargo that, when combined with the lung-targeted LNPs I developed, reverses at least one major lung disease in mice. Again because mice have sharply different lung physiology from humans, I plan to test it in ferrets. As with my previous work, this will be with Dr. John Engelhardt, the world authority on ferret lung biology and a professor at University of Alabama Birmingham. This Manifund funding will enable this important preclinical study and, if successful, open the door to eventually bringing healthy lungs to millions of people.

Why are you qualified to work on this?

I am a postdoctoral fellow in the lab of Dr. Daniel Anderson at MIT working on pulmonary gene therapy. The Anderson lab is one of the top academic LNP research labs in the world and has spun out numerous highly successful companies; hopefully we will spin out another one based on this work to bring it to clinical trials and patients. I personally have published two co-first author papers in Nature Biotechnology and Nature Nanotechnology focused on pulmonary gene delivery, and also am a co-author on multiple other projects focused on pulmonary delivery.

I also have cystic fibrosis (CF), a very nasty genetic chronic lung disease, and I’ve been studying CF my entire life, which means I’m independently an expert about lung biology and LNPs. My Ph.D. was focused on the biophysics of mucus layers; the lung mucus layer is a major barrier to inhaled lung delivery. Curing lung diseases has been my mission in life approximately forever, and this will help advance that mission.

Also, my top LNP candidates, FO-32 and FO-35, were identified using a deep learning model that I developed. I expect my AI capabilities to be generally helpful for leveraging AI in biology moving forward.

How much money do you need?

$80K will allow for a full ferret experiment to be run with our lead indication. More money would allow for more extensive safety testing, essential for taking a therapy to patients, or testing our therapy for a second lung indication. I can't guarantee there will be a second indication as I am currently testing that in mice right now, and I will update here if the answer turns out to be yes.

References

Witten, J.,* Raji, I.,* Manan, R. S.,* Beyer, E., Bartlett, S., Tang, Y., ... & Anderson, D. G. (2024). Artificial intelligence-guided design of lipid nanoparticles for pulmonary gene therapy. Nature biotechnology, 1-10.

Jiang, A. Y.,* Witten, J.,* Raji, I. O., Eweje, F., MacIsaac, C., Meng, S., ... & Anderson, D. G. (2024). Combinatorial development of nebulized mRNA delivery formulations for the lungs. Nature nanotechnology, 19(3), 364-375.

*Co-first authors