First-in-Human Mitochondrial Transplant!
Excited to share some new science in pre-print this morning! We have completed the world's first intravitreal autologous mitochondrial transplant in a human.
Let's break down what we did and what this means, even starting from the title (!). If you’d like to skip straight to the preprint, you can find it here: https://www.researchsquare.com/article/rs-10622019/v1
Intravitreal: injected into the vitreous humor of the eye
Autologous mitochondria: mitochondria that are genetically identical to the transplant recipient and made from their own tissue
Transplant: to take from one place and put into another place.
So let’s dig in: A young person who had survived a severe brain bleed was under our care and recovering from their injury when we noted that they were experiencing vision loss. This happens in some severe circumstances when enough pressure builds up because of the bleed that the optic nerves (which kind of sit at the bottom of our brains) can get crushed between the base of the skull and the brain itself. In this young stroke survivor, we noted that they were losing pupillary responses day-by-day and their neuroopthalmologist noted total blindness. When optic nerve crush occurs, this is frequently a situation where there are no great options - vision loss is expected to be permanent and there are no known therapies. Our team had been following mitochondrial transplant research and after reading this paper:
https://nature.com/articles/s41586-026-10391-0 we decided it was worth giving it a shot. We reached out to the FDA and received emergency authorization in record time and began the process. Step 1 was to get tissue from our patient that could be used to extract mitochondria. Working in collaboration with the brilliant
Dr Jim McCully from Harvard, we decided on using muscle tissue and followed his methodology (overseen by Jim himself!) for extracting mitochondria from those cells: https://nature.com/articles/s41598-017-17813-0 We were also beyond fortunate to have Melanie Walker fly in from Seattle (one of the few people in the world to have tried mitochondrial transplant of any kind in a stroke patient) to share her wealth of knowledge and experience with us. Procedure day came along: we took a muscle biopsy from the quadriceps (thanks @chriskellnerMD!), extracted mitochondria from the muscle, isolated the mitochondria and, thanks to our brilliant GMP facility at Mount Sinai led by Mansi Saxena, we put those mitochondria into a syringe for our rockstar Dr Gareth Lema to inject into the right eye of our patient. The next day, we did all over again for the left eye.
Now, as many of you who follow me may know, when we do something first-in-human, yes we are hoping it will work, but first and foremost we're hoping to establish safety. One of the biggest safety concerns we were fielding in this whole process was whether injecting mitochondria into the eye would cause an immune reaction. Now, mitochondria themselves are actually famously able to fly under the radar of the immune system and NOT cause an immune reaction, but if the mitochondria get damaged and mitochondrial DNA is released that is, theoretically, a different story. So our first order of business was to prove that we could perform this transplant without causing a large immune reaction in the eyes and we hit that deliverable handily: no sign of immune reaction in either eye, and our patient handled it like a champ.
What was super-encouraging and exciting, though, was that within 48 hours of each transplant we started to see pupillary responses returning to BOTH eyes. We went from pupils that were absent of response to light, to seeing measurable pupillary responses in both eyes (measured with a device called a 'pupillometer'). We also noted post-transplant that a visual-evoked potential emerged in the brain in response to visual stimuli, meaning that the brain is now responding to visual stimuli that are being presented.
Now, although we saw a really exciting initial response, we also saw that response fall off with >100 days of follow up. Pupillary responses remained higher than they were at baseline, but not as high as we saw them go. So what is next in this exciting work? We are in the process of getting more procedures lined up for this patient - it is not practical to take a chunk of muscle every time we want to do a transplant, so we're working on some alternate ways to achieve this now and will be resuming the work ASAP. Also, there are so many conditions that can benefit from this work - including other forms of brain injury and neurodegeneration, but also #LongCOVID, #MECFS and other complex chronic illness where energy limitation is a problem. We will be aiming to get an active research arm off the ground on this ASAP. Also, hopefully you can see from this thread that this procedure was successful because a collection of dedicated and clever people worked together across disciplines to achieve something very technically difficult. I cannot fully express the awe and gratitude I have for my co-authors.
Finally a huge thank you to our patient and her family. You all are, to me, on the same tier of courage and determination as astronauts exploring the great unknown with us. We will not easily forget the faith and trust that you placed in us to move this research forward for the millions who can benefit. Feeling enormous gratitude to a whole lot of amazing people who helped us make the impossible possible today. Much more to come!
— Dr. David Putrino
