we were aware that Molly had a vision impairment because when I was breastfeeding Molly she would look away from me to see a light somewhere else in the road when their daughter was just a few months old Laura and Ryan Troxel got heartbreaking news Molly had symptoms of an inherited disease a form of blindness she would probably lose what little sight she had by the time she became an adult I was devastating I remember trying filter up now they could've auditor just knowing that your daughter's not gonna be able to see Molly's blindness was due
to a mutation in the genetic instructions for a protein in her eyes ever since biologists first cracked the genetic code they imagined that someday this knowledge would help cure diseases like Molly's bingo that time has finally come when I first realized that we could make a blind dog see it was the first hope that we could actually do the same thing to children and make blind children see this is the story of how gene therapy developed from a dream in the lab to a revolution in medicine [Music] your injections look fabulous yeah that looks really
exciting I mean one hurting stuff to show you actually I first began to be interested in gene therapy when people began to clone genes and transfer them to animals this was in 1980 they were transferring genes to mice and altering their appearance and their growth and I realized wow this approach could be used to treat humans that's great and I realized this is what I want to do most genes are instructions for producing proteins that perform important functions in different cells of the body inherited diseases come from mutations in genes those mutations result in the
production of a faulty protein or sometimes no protein at all the principle of gene therapy is to provide cells with a corrected copy of the mutated gene that will produce the functional protein the big idea of gene therapy is that you're treating a disease at its root you are stopping the disease and it's track by altering the instructions that the cell is given the benefits are that one can potentially correct the basic problem that is causing the disease and allow the cells to function normally and thus allow the person to function normally I met my
husband in medical school and he knew early on that he wanted to study neuroscience and his biggest interest was in the retina the retina is a light-sensitive layer of neural tissue at the back of the eye it converts light energy into signals that are carried to the brain by the optic nerve people don't realize the retina is a very integral part of the brain and essentially what it is is the brain is squeezed out like toothpaste into the eye sockets and it forms a film and that's the camera film the retina that you and I
see with McGuire's focus on eyes and Bennett's expertise in genetics naturally came together in the 1980s while they were still students Maguire wondered if blindness might be treated with genes albert asked me in medical school whether the eye would be a good target for gene therapy and I said yeah sure what I didn't tell him is we didn't know any of the pieces that we needed to be able to do this there had been no genes identified which when mutated caused that condition we didn't know how to clone those genes if I had known all
the issues I probably would have walked away it would take decades to assemble the necessary tools and know-how but the eyes were a good potential target for developing a gene therapy eyes are easy to access and to eyes means that in an experiment one can be treated while the other acts as a control for Bennett and McGuire the next question was how can you get the corrective genes into the cells you want to treat it may seem crazy but viruses are now used because viruses have evolved to do what they do really well and that
is to move DNA or RNA across cell membranes viruses contain packets of genetic information they can invade cells and deliver their genes inside then they hijack the cells machinery to make copies of themselves scientists strip away the virus's harmful genes and those needed for the viruses to replicate then they insert a copy of a corrective gene attached to the gene our regulatory sequences which direct it to be expressed in specific cells next scientists inject huge numbers of the modified viruses into the tissue that needs the therapy the viruses invade those cells and deliver the corrective
gene but without replicating our first animal model for testing the ability to use viruses to deliver DNA was the mouse through the 1990s Bennett and her collaborators tested different types of viruses and methods for injecting them into Mouse eyes until they showed the procedure could work but mouse eyes are small compared to human eyes you can imagine the surgery to deliver a gene to a mouse eye is a lot different than if you are going to inject the eye of a human which is a hundred times bigger to be sure that a sufficient number of
genes could be delivered and expressed in human sized eyes the researchers needed to develop procedures in a large animal model one breed of dog turned out to be the perfect model Briard Shepherds have eyes about the size of humans and remarkably some Briard Shepherds suffer from the same form of blindness that's a leading cause of blindness in children the couple adopted this pair of dogs after they retired from work in the lab the free yard dog has the exact same genetic condition as humans who have child onset blindness called labor amaurosis so they match up
almost perfectly with the human conditions in both humans and dogs labor amaurosis can be caused by mutations in a gene called rpe65 as a result of the mutation the light detecting cells in the retina called photoreceptors progressively malfunction and die the symptoms typically show up in infancy Molly Troxel inherited the disease-causing mutation from her parents they each have one working copy of the rpe65 gene so their vision is fine but in each parent the other copy contains a rare mutation that leads to a non functioning protein Molly inherited two mutated copies of the rpe65 gene
one from her mother and one from her father so her cells have no functioning rpe65 protein the odds of two people with a rare mutation in the same gene having a child together our remote indeed you know her and I were just somehow our genes ended up creating Olly which is a great thing but you know with her having the eye disease is just a really rare thing also I think Molly was around age 6 when they were able to define that she had the rpe65 mutation gene therapy would be an option for her someday
so that was a lot of wonderful hope the research that could turn hope into reality came together with the help of Briard shepherds it wasn't until we had the Briard dog that we actually had all of the pieces in place the know-how had to deliver the genes in the appropriate animal model which is critical but while Bennett and Maguire assembled the components for treating labour amaurosis in dogs researchers had already begun testing gene therapies for other diseases on humans in 1999 tragedy struck Jessie gyal singer entered a gene therapy trial at the University of Pennsylvania
for the treatment of a rare liver disease doctors injected Jessie with a virus that carried copies of a corrective gene but his immune system reacted to the viral invasion with overwhelming force damaging his organs for days after the procedure Jessie Kell singer died he was 18 this was a tragic event for this young man and his family but it was also a tragic event for the field of gene therapy itself because everything came to a screeching halt people withdrew their interest and their support for gene therapy there was no more funding with human clinical trials
shut down Bennett EMA Guire pushed on with attempts to restore sight in Briard Shepherds dogs with mutations in the rpe65 gene would grow up to be blind unable to navigate simple environments so we took advantage of all the things that we had learned over the preceding decade or so and injected three puppies then they waited when the therapy restores some sight to the dogs or wood failures send the scientists back to the drawing board at the two-week time point after injection I got a call from the animal facility the vet tech taking care of them
said gene they're watching me as I walk through the facility I think they can see and they could and it was miraculous it was absolutely just one of the most exciting moments I've had in science it was the first hope that we could actually do the same thing to children and make blind children see Bennett McGuire and their collaborators successfully repeated the experiments with more dogs the next step would be to try it in people but in the wake of the Gelson Gore tragedy moving forward with human trials would be difficult there had been a
general sense that this was a therapy that was not ready for prom town that there were too many things we didn't understand and that it was not ready for development all the companies that had been involved in gene therapy were either turning away from it or they were failing and now they want several examples of this but as companies left the field gene therapy pioneers like Katherine High persisted in 2001 she was setting up a gene therapy facility and looking for Canada diseases when she came upon Bennett's work so I was always looking for things
where there was good proof-of-concept in a large animal model and she clearly had it when we had our facility set up I went over to talk to her she walked into my office and I looked up and she said gene how would you like to run a clinical trial it's just I was totally floored I was not expecting that at all and so that was the beginning of a whole infusion of energy and enthusiasm and support and led to incredible success it took Bennett and HI years to adapt the virus delivery system to be safe
and effective in humans in 2007 they recruited the first patients for human trials in 2013 the trachsel's threw a party for Mali now 11 she was about to be enrolled in a later trial I was really excited and I was scared because you know it's surgery on your eyes but then I was thinking you know it's gonna be okay he's gonna work molly was gung-ho she was going to do this she wanted it I was afraid the hope was that she would have more vision but there's a possibility that it could make her vision worse
the surgeon first injected one of Molly's retinas with six drops of a liquid containing billions of gene carrying viruses later if the procedure worked they would inject the other eye each virus contained a copy of the rpe65 gene the virus has invaded the retina cells and delivered their genetic payload the cells machinery produced the rpe65 protein to restore function when the patch came off Molly couldn't tell if anything was different but then I saw the moon well Wow Molly you can see that for her to see the moon and stars things you would take for
granted was just huge for us now there's this no stoppin here I think the biggest surprise for me is just her independence she can ride her bike up in the circle without us you know being right there and you know pins and needles that she's gonna hit a mailbox or something even though to an outsider she still looks visually impaired I'm so thankful that she can see better and if nothing else that it stopped the progression of this disease I was hoping for perfection but that's hard to do but what I have now is perfect
I feel extraordinarily lucky to actually see our research move from the bench all the way to treating humans and then see these humans benefit all science builds on previous science and science involves so many different areas of expertise this whole study is a perfect example of the importance of collaboration in science more than 40 patients most of them children have taken part in rpe65 clinical trials with excellent results in 2017 rpe65 gene therapy was recommended for approval by a panel of the Food and Drug Administration for the treatment of congenital labor amaurosis this success brings
therapies for other inherited diseases one step closer to reality [Music]
