I wonder if it's a statistically significant uptick.

It does take a lot. The hope is that all the companies doing BBB permeable AAVs like Apertura, Capsida, Sangamo, Voyager etc. will find something that works 10-100-fold more efficiently.

Ultrasound BBB opening in large animals (or humans) is doable but somewhat complex. I do think the prices and complexity will go down over time for both gene delivery and BBB opening.

Doing whole brain BBB-permeable gene delivery + with FUS release of synthetic markers could allow to study multiple sites without surgery and monitoring intracellular gene expression. e.g.
pubmed.ncbi.nlm.nih.gov/39110811/

That would be neat. Hong Chen at WUSTL has done some pioneering work in using FUS to release native proteins from the brain into the blood. There's non zero chance that native proteins carry sufficient information. If not, then the synthetic markers probably will, but would need gene delivery.

What do you want to study? I am always curious about what are the experimental hurdles people have. I am wondering if it site-specific liquid biopsy would be useful for you. It's much more technically complicated but can study different regions on different days.

There are some hurdles for human translation eg need for exogenous gene delivery. There are also ways to mitigate them. If our bright focus grant works out it should make translation realistic. There will be more work on optimization in nhps like higher signal, longer duration, recording c-fos etc

Author list:

Thanks Mark. I think we were surprised it worked so robustly. Still lots of work to do, in mice we could do orders of magnitude signal and track c-fos, arc etc. Next paper, if we can get the funding. This was done on a shoestring.

www.biorxiv.org/content/10.1...

Lead author: Manwal Harb, who also contributed to engineering AAV.FUS, vector optimized for noninvasive site specific gene delivery to the brain.
www.nature.com/articles/s41...

Work supported by The G. Harold & Leila Y. Mathers Charitable Foundation

Jordan, we missed you at the ACS! I hope you're doing well

i think it would be for more surprising if the mixture wasn't racemic...

They are about a half of what we get paid here, but money isn't everything.

this book brings back good memories!