📷 OHSU Casey Eye
Journalist: Haleema Ahmed
Haleema Ahmed:
Hello everyone and welcome back to SciSection. I’m Haleema, your journalist for this week, and today we are delighted to have Dr. Mark Pennesi. Dr Pennesi is a Professor in Ophthalmology at Oregon Health & Science University and Chief of the Ophthalmic Genetics Division at the Casey Eye Institute. He is interested in retinal diseases and most notably, Dr. Pennesi led the first-ever CRISPR gene editing procedure to restore vision in partially blind individuals. Thank you for joining us.
Dr. Mark Pennesi:
Thank you. It's a pleasure to be here.
Haleema Ahmed:
Before we get into some of the research that you have done, I have a couple of rapid fire questions for you pertaining to the eye and also, what it is that you do everyday. Firstly, what fact about the human eye do you think is the most shocking or interesting?
Dr. Mark Pennesi:
I think one of the most interesting facts about the eye is that when we look into the eye and look at the retina, which is the part of the eye that senses light, the retina is technically part of the brain. So, we are actually directly looking at the brain when we view the retina.
Haleema Ahmed:
That is really cool. Why did you decide to pursue a career in medicine and subsequently, a career in ophthalmology?
Dr. Mark Pennesi:
I started off as a biomedical engineer in college and I always had an interest in science and trying to come up with new cures for diseases. That led me to applying for an MD/PhD program at Baylor College of Medicine. I got a PhD in neuroscience where I studied animal models of retinal degeneration and became very interested in genetic eye diseases, primarily because there were no treatments at the time for those diseases. And even today, many years later, we are only now starting to have the first successful therapies for these diseases. It has been a very long journey, but it has been a very rewarding one.
Haleema Ahmed:
Speaking of some of these diseases, you led the first ever procedure in which CRISPR was used to repair mutated genes in a living human. What exactly is CRISPR?
Dr. Mark Pennesi:
CRISPR is an acronym and it refers to a larger system called CRISPR-Cas9. You can think of this a little bit like for bacteria, they have an immune system to protect themselves from viruses. When viruses infect bacteria, they inject their DNA into the bacteria and the bacteria actually have a series of enzymes called Cas proteins that can cut up that viral DNA and prevent the infection. As they can incorporate that DNA into their own genome, such that it can form a memory bank to efficiently cut up that DNA in the future. What we do is we co-opt these mechanisms from bacteria, which involve a way to bind specific parts of the DNA and then bring a protein that will cut the DNA. We use that for our own purposes to edit the human genome.
Haleema Ahmed:
Has CRISPR ever been applied to ophthalmology previous to this study?
Dr. Mark Pennesi:
Not in humans. Certainly, it had been tried in animal models and so there was a lot of hope that it could be successfully utilized in people. But this was the first time that we were treating a patient in vivo with CRISPR.
Haleema Ahmed:
The study that your team conducted, referred to as BRILLIANCE, aimed to repair gene mutations, which cause a form of inherited blindness. Speaking particularly about that type of blindness, how does it come about and how does it impact the lives of patients who have it?
Dr. Mark Pennesi:
The name of the disease is called Leber congenital amaurosis type 10 and this is a rare genetic eye disease. What happens in these patients is they have a mutation in a gene that codes for a protein called CEP290. This protein is important for the photoreceptors. It helps develop the outer segment of the photoreceptor, which is the part of the cell that actually senses light. You can kind of think of it like a little antenna on the photoreceptors. When you don't have this protein, that little antenna does not extend and the cell cannot detect light. But what is really interesting is the cells are still there but they are just not working. So patients with this disease are born with very severe vision loss. These patients may only be able to tell if a room light is on or off, but they cannot read any letters. They have very, very poor vision and over time, it gets worse and many will ultimately lose all of their vision. If you look at the mutation in this gene, it is very peculiar because it actually occurs in the intron of the gene, which is a non-coding portion of the gene. What it does is it essentially creates a little stop sign in the pre-mRNA, such that the full length protein doesn't get made. What the goal of the trial was, was to use CRISPR-Cas9 to essentially cut out that stop sign or cut out the mutation, such that you can then get full transcription and a normal protein. Hopefully, that would restore the function to those retinal cells that are still remaining but not functioning properly.
Haleema Ahmed:
Now that we have a background on this form of blindness and how it is that CRISPR is used, how exactly was the BRILLIANCE case study conducted in terms of: where did this idea come from? What were the steps involved in editing that particular gene? What did the surgery actually involve?
Dr. Mark Pennesi:
Well, I cannot take credit for the technology. That actually goes to some of the Nobel prize winners, such as Jennifer Doudna, who really studied this in the lab. This technology permeated to the company Editas Medicine which is the sponsor of the trial. They developed the actual gene therapy vector to deliver the CRISPR machinery. What we did was we were the ones who found and recruited the patients. We always start in adult patients and usually in patients who have very severe vision loss, because early on with therapy, the primary goal is really safety. We want to make sure that the treatment is safe first. Once we know that the treatment is safe, then we can treat less severe patients and younger patients. Ultimately, the hope would be to treat children. With the very first patient, we always start at a very low dose and we are very open to the patient and tell them that there is a good chance that this may not work. This is essentially an experimental therapy. You are doing this possibly for just the benefit of other people so you may not benefit yourself. We often have to really look for patients who are very altruistic and understand that there is some risk involved and they may not benefit. Fortunately, we do find those people. We were able to treat the first patients at the Casey Eye Institute and also my collaborator, Eric Pierce at Mass Eye and Ear has been treating patients as well. What we found was with a very low dose, we did not see any concerns with safety. In fact, one of the patients even noticed some improvement in their vision. Even though they had very poor vision, they could see different colored lights at a dance party better than before. What was really exciting though, was when we went up in the dosage and treated more patients, then we actually started to see improvement in visual acuity. The ability to read letters on the chart, as well as a patient's ability to navigate a maze that we created to test their vision and just the overall sensitivity of the retina. This is still an ongoing trial and these results are very preliminary, but they are nonetheless very exciting and we are moving forward to treat patients at higher doses. We are hopefully going to start treating children because we have some reason to believe that children may respond even better. They have more preservation of the retina, their visual cortex is more plastic such that it might be able to accept new information better, and they might even show a more accentuated response to the therapy.
Haleema Ahmed:
Definitely the results do seem very promising. As you mentioned that this particular form of blindness can get worse as people age, it would be fantastic if it was successful in these younger patients that you are now planning to pursue treating. How do you see CRISPR being further applied to other retinal diseases and forms of blindness in your work?
Dr. Mark Pennesi:
I think that the first therapy is always the hardest but it provides the proof of principle that if you can treat one gene, then it is likely you are going to be able to treat other genes. When we look at inherited retinal degenerations, there are over 300 different genes that can cause inherited retinal degenerations and CRISPR may not be the right treatment for all of those genes, but it is going to be the right treatment for some of those genes. If we are successful in this, that is going to open the door to using gene editing in other retinal diseases.
Haleema Ahmed:
When it comes to investing in this research, definitely the results and potentiality that CRISPR could have in treating a lot of these diseases is very promising. But in the same end, what concerns do you think may arise with gene editing in vivo?
Dr. Mark Pennesi:
There is still a lot we do not know about what the long term effects are. For example, we do not know how long the treatment will last. We think that it should be permanent because you are editing the gene and once you have edited it, it should not go backwards, but it is possible that that might improve vision, but it may not stop the progression of the disease. That is something that we are going to have to study over time to see if correcting the gene really does stop progression. There are always concerns with any kind of gene therapy about inflammation most in the short term, but we need to look at that over time as well.
Haleema Ahmed:
And on that note, thank you so much Dr. Pennesi for joining us today to share your incredible work on using CRISPR to treat blindness. To keep us with his incredible research check out Oregon Health & Science University.