Christine Kay, MD, a Vitreoretinal Surgeon with an area of expertise in Inherited Retinal Disease, explains Achromatopsia, its severities, and the clinical gene therapy studies that are being conducted. Christine practices at Vitreoretinal Associates in Gainesville, Florida.
Interview conducted by Ivanhoe Broadcast News in June 2017.
I wanted to ask you a little bit about the condition, achromatopsia?
Dr. Kay: Achromatopsia is a rare inherited retinal dystrophy involving cone cells in the retina. Patients with achromatopsia lack color vision. They have markedly reduced visual acuity, and they are extremely photosensitive or sensitive to light. They have a form of day blindness, due to this severe light sensitivity.
When does this normally onset? From birth?
Dr. Kay: Yes, it is congenital-onset; meaning patients are affected from birth. They are diagnosed usually early and the condition is relatively stable, meaning it does not drastically progress throughout a lifetime.
Okay, once they are diagnosed that is usually the vision that they are dealing with?
Dr. Kay: Correct, and the average visual acuity for a patient with Achromatopsia is in the 20/200 range.
What treatments currently exist for achromatopsia?
Dr. Kay: There are no approved treatments at this time for Achromatopsia.
Can you explain what therapies you are investigating?
Dr. Kay: I am studying gene therapy for achromatopsia, funded by a biotech company called AGTC.
Can you explain gene therapy?
Dr. Kay: Gene therapy means that we replace the mutated copy of a gene with a normal copy of a gene. Genes are responsible for expressing proteins, which are essential for all the functions of cells in our bodies. In order to deliver the gene of interest to a cell, we typically use a non-replicating virus called the viral vector. If you have heard the term “vector” we are talking about typically a virus. We remove the host DNA from the virus so it does not have the capacity to make you sick, and then we insert the DNA of interest – in the case of CNGB3 achromatopsia we insert the CNGB3 gene into the viral vector. Then we have to get that viral vector into the retina. This is done surgically by a vitreoretinal surgeon because at this point the gene does have to be directly delivered to the retinal tissue with a subretinal injection which is an injection directly under the retina.
You said at this point, down the road what would the hope be or is there a procedure that would make it a little easier on the patient?
Dr. Kay: Sure, other methods of delivery are being studied, and I have done some work on this myself as well as many researchers here nearby at the University of Florida and many other sites throughout the United States who are all working on other approaches to gene therapy that would not require a subretinal injection. You can imagine if you could avoid directly touching the retina tissue and instead inject on top of the retina and avoid detaching or touching the retina with a cannula, which probably would be mechanically less invasive to the eye. There is an approach called “intravitreal” where we inject inside the eye through the eyewall. Intravitreal injections are actually commonly done in a clinical setting: in my typical retina clinic I inject multiple patients on a given day, 20-30 patients a day depending on my number of patients in clinic that day, with an intravitreal injection (for other medical reasons than gene therapy). Intravitreal delivery has not yet shown efficacy for achromatopsia, although AGTC is currently doing a gene therapy trial for X-linked retinoschisis, which is another inherited retinal disorder and they are intravitreally injecting that vector into the eye; and that is very exciting. If we can translate that into other genetic retinal disorders and create these viral vectors that have the capacity and are strong enough to get through the retina and get to the cells of interest, then that would be wonderful and certainly less invasive to the eye. But again, at this point for achromatopsia the cells that we have to target are cone cells, responsible for decreased vision and color vision, and those cells are in the very bottom layer of the retina and so we have to surgically get under the retina in order to target those cells.
How many people are in the trial, you said that this is a multicenter trial on it’s a phase 1, phase 2, how many people have you had and over what period of time?
Dr. Kay: It is a good question, and it depends. The length of the trial is variable depending on how long it takes us to enroll all the patients and how long it takes to treat all the patients. It could be years until we have treated the number of patients set out in our protocol. Our protocol is 24 patients that will be treated: nine patients in the first three cohorts and 15 in the final cohort. It is a dose escalation trial, we will treat the smaller dose followed by a medium dose, followed by a higher dose, and select the appropriate dose then we will treat the remaining 15 patients with the optimal dose. Once we have the data from those 24 patients we will be able to analyze all of our data and be able to present our final results in a scientific forum.
Dr. Kay, what is the hope down the road for this disease?
Dr. Kay: The hope for this disease and many inherited retinal diseases is being able to finally provide a treatment. Many inherited retinal disease patients have come to clinics for decades and they have been diagnosed with diseases, whether it be retinitis pigmentosa, Stargardt disease, choroideremia, X-linked retinoschisis, achromatopsia … and they have been told that they are blind and there nothing we can do. I cannot tell you how many patients still come to my clinic and have had that discouraging discussion by even good ophthalmologists, because even currently most of our ophthalmologists are not aware of the details of gene therapy and which diseases are being treated and the new technologies that exist, because this is a new field. But it is very exciting, in the last 10 years there has been an explosion of gene therapy trials and clinical research efforts to that effect, and the hope would be not just for achromatopsia but for many inherited retinal disorders that we can finally have a treatment to offer these patients. I do firmly believe this or I would not be doing this field. I believe we can significantly and positively impact the lives of our patients; again not just with achromatopsia but with many inherited retinal disorders with gene therapy.
Can you speak on Tara’s case a little bit?
Dr. Kay: Achromatopsia is a really interesting condition, because there is not much variability between patients as with other retinal disorders like Stargardt disease, or like retinitis pigmentosa. Tara, like many of my patients with achromatopsia, is significantly affected by decreased vision, by color blindness, and by her light sensitivity. Again, along with all my patients with achromatopsia those are the top three complaints. Now these three complaints are typically things that patients are struggling with on a daily basis. A lot of these patients have developed compensatory mechanisms and have learned how to accommodate, or learned how to deal with their disease and how to cope with these disorders; but again they are still struggling with this every day. The possibility exists to be able to actually treat them and improve some of those symptoms for them and improve their vision; potentially improve and create color vision, which is a very exciting phenomenon. If a patient could actually suddenly see color, learning how to interpret that with their brain, of course, is an interesting phenomenon as well. We do not understand fully how the brain will learn to interpret color if color has never been seen, but it is a very exciting field right now with the potential of being able to improve not only visual acuity and color vision, but to significantly impact their light sensitivity and improve their daily function. These things would really make a difference to these patients who deal with these issues on a day to day basis.
Help me describe to our viewers, what it is that you are doing in your clinical trial?
Dr. Kay: In this clinical trial the patient is first seen and screened and they are extensively tested. A lot of the patients who are in the treatment trial right now were previously involved in our national history study, which was also funded and sponsored by AGTC, the biotech company who created the novel, investigational drug that we are looking at. These patients are screened, they are tested, they have electroretinograms, color photos, and all these advanced photos and tests we do here in the retina clinic. Usually they undergo a day or two of testing, and of course we confirm their genetic mutation and they have genetic testing reconfirmed. They have to have two mutations in the given gene for the clinical trial. The day of surgery is of course the highlight of the clinical trial here. I am the vitreoretinal surgeon here at my site, and I am also the evaluator for these patients, along with two of my other partners at Vitreoretinal Associates in Gainesville, Florida. On the first patient that I treated, Dr. Roseman scrubbed in with me to assist me with the subretinal injection portion of the procedure, as an assistant is required to push the syringe containing the vector while the surgeon (myself) holds the cannula under the subretinal space. We did the surgery here at our North Florida Regional Hospital, at the outpatient surgi-center called the Pavilion Surgery Center. The patient is usually put to sleep for the surgery since it is a relative long case, and because there is a lot going on in the room. We have to get the viral vector prepared by the compounding pharmacy and brought over in a certain amount of time, and do a vitrectomy, which is a typical retina surgery done by any vitreoretinal surgeon. Of course, this is done in a typical sterile operating room, and the patient is asleep. The point of the case where the gene is delivered is called a subretinal injection, where a very small cannula is used and is placed through one of the ports we created in the side of the eye wall, and we place this cannula into subretinal space in the macula and we inject the vector, again the virus carrying the CNGB3 gene in this trial. We inject it directly under the retina and then finish the vitrectomy and close the incisions in the eye wall. The patient wakes up from the surgery, and we follow them very closely postoperatively.
How long are they followed then?
Dr. Kay: For the first year they are followed extensively. We see them the day after surgery, one week postoperatively, one month postoperatively, and then three months, six months, and nine months, and a year. They are followed for I believe an additional four years out to a five year follow-up date.
Is there anything Doctor that I did not ask you that you want to make sure people know?
Dr. Kay: It is important to emphasize to patients or to family members that these clinical trials are ongoing and possibly the optometrist that you are following up with, or the ophthalmologist you are following up with might not even be aware of some of these trials since diseases like achromatopsia are quite rare and gene therapy trials relatively innovative. It is important for patients to sometimes take the initiative. A lot of my patients actually contact me, contact AGTC; look up trials at clinicaltrials.gov and I would actually say, ironically the majority of the patients that have gotten involved in this trial have initiated that involvement themselves; as opposed to them being directly referred by an ophthalmologist. And that is probably is still because the lack of awareness. I present a course at Academy of Ophthalmology every year with some co-faculty to teach ophthalmologists about updates in the field of clinical retinal gene therapy for inherited retinal diseases, but this is not something that is necessarily taught to ophthalmologists in our residencies, fellowships, depending on when you train because these are relatively a new therapies. I would emphasize to patients and family members that if you have a suspicion that you have an inherited retinal disease because of what you are hearing and other things that you read then investigate that further and continue to investigate until you get a diagnosis. If you haven’t had genetic testing yet ask why, because genetic testing right now is really becoming the standard of care. If you have not and you know you have an inherited retinal dystrophy and do not know your genetic mutation, or have not been offered genetic testing you can pursue genetic testing multiple ways, even ways that might be free-of-cost due to grant coverage through Foundation Fighting Blindness or Spark Therapeutics and other such organizations. If you think you need therapy and that you might be a candidate for a clinical trial then please contact us, we are listed on clinicaltrials.gov, or contact AGTC; their contact information is directly listed on their website or on clinicaltrials.gov. Patients are quite frequently directly contacting either the investigator or AGTC to see if they can be enrolled in this trial and screened for the trial. Ultimately, without patients we would not have research, we would not have updates and treatments and potential cures in the future. And without investigators motivated to study these diseases and industry or nonprofit organizations or government funded agencies willing to fund research, we would also not have these trials. It is important for us all to continue to work on this together and hopefully in the future be able to offer safe and effective therapies to patients for previously untreatable eye diseases.
END OF INTERVIEW
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