Low Vision News: Edition 4 with Dr. Maguire

GENE THERAPY TREATS CONGENITAL LEBER’S AMAUROSIS
Interview: ALBERT M. MAGUIRE,MD

ALBERT MAGUIRE,MD is a Clinical Associate of the Division of Pediatric Ophthalmology at Children’s Hospital of Philadelphia. He is an Associate Professor of Ophthalmology at the University of Pennsylvania and Director of the Retina Service of the Division of Ophthalmology.

Follow up:

Editor: About ten years ago, there was a small article in the New York Times about a dog named Lancelot that had a disease similar to Leber's Congenital Amaurosis. I was astounded to read that the disease was actually reversed by genetic engineering. Why did you pick this disease?

Dr Maguire: Lancelot put our research on Prime Time. Leber’s chose us,we did not choose it. Congenital Leber’s Amaurosis has all four requirements for a study: first, you need a disease with an animal model to prove that your method works and that your science is sound; second, this disease is affected by one gene and it is relatively simple to correct the defective gene with a healthy one; third, the disease is very simple biochemically. A single enzyme is missing for the process that converts Vitamin A to rhodopsin, the photopigment that is necessary to see. Once the enzyme is produced in an eye, the disease is reversed. Finally, the disease itself is slow and relatively non-toxic. Many of the cells in the retina are still alive and capable of being resuscitated. Once the enzyme is introduced, the cells resume their normal functions - vision can be partially restored and further deterioration can be prevented.

Editor: Are there any other diseases that might also be cured by this method?

Dr Maguire: Gene therapy is a very effective way to deliver a protein or peptide. If you have a product that is therapeutic, gene therapy can be used to deliver that protein/peptide product. You could use the same technology to make human insulin or to deliver a molecule which would stop the advance of wet macular degeneration. We are now looking at Stargardt’s Macular Degeneration. It is the congenital form of macular degeneration that occurs in children. It looks promising because it is affected by a single gene also. Other forms of Leber’s and the recessive form of retinitis pigmentosa may also be helped by this technique in the future.

Editor: Will gene therapy restore function if the retina has deteriorated?

Dr. Maguire: Most of the time gene therapy will not reverse the damage, but it can prevent further loss of sight. Hopefully, we will find other eye diseases that are caused by a lack of an enzyme. These conditions can be reversed to restore eye sight.

Editor: Can you explain the procedures you use to do gene therapy?

Dr. Maguire: My expertise is retinal surgery, especially in children. At the time of surgery, I am given a biologic gene therapy agent. It is a solution containing virus particles that are manipulated so they do not produce disease. They contain DNA that codes for the therapeutic protein, and the virus then ‘piggybacks’ our therapeutic DNA into the patient’s retinal cells. Once the DNA is delivered, the cells begin to produce the therapeutic protein and function is restored. My job is to perform a vitrectomy, removing the jelly-like material in the back of the eye and replacing it with saline. Then I inject the biologic agent under the retina, where it can get to the photoreceptors in the eye.

Editor: How do you know that the biologic material will not migrate under the pigment epithelium and travel through the blood vessels in the choroid and ultimately affect the brain?

Dr.Maguire: We have done experiments using a marker, and have also tried to detect the vector by other means. In our marker experiments, we use a protein that is produced by jellyfish and is not found in any other animal species. This protein glows when blue exciter light beam is shining on it, just like fluoroscein dye. We use a vector which contains the jellyfish DNA,which codes for this protein, then look for it with the fluorescence. We have examined surrounding tissues as well as samples from brain and other tissues and have found no leakage, i.e., no jellyfish protein where we don’t want it. With this vector, using extremely sensitive techniques, we cannot detect transfer to the brain.

Editor: One thing that you and I have in common is that we both work with our wives. What part does your wife, Dr Jean Bennett, have in your joint research project?

Dr. Maguire: Dr Jean Bennett is the chief science officer. She is responsible for all aspects of the research including conducting the immunological studies, monitoring and collecting specimens, designing all the experiments, and monitoring visual changes of the patients by using pupillometry. She even drives patients to and from the airport.

Editor: You sound like you have the perfect team. Please tell me why you use pupillometry?

Dr. Maguire: Leber’s Congenital Amaurosis is a rapidly progressive disease that affects babies and very young children. We wanted an objective measure that shows us if the treatment is working. The retina in LCA patients is too weak to generate an ERG signal, but it can still drive the pupils to react to light. If, after surgery, the pupil reflexes improve in the treated eye, but not in the untreated eye, the only possible explanation is that the treatment improved the retinal function of the treated eye. In essence, we create a Marcus-Gunn pupil ( APD) in the untreated eye by making the treated eye stronger.

Editor: What are the steps that you must take to go from research to a treatment?

Dr. Maguire: The first step began in the lab. We had to formulate a treatment strategy to address the biochemical defect which causes LCA. We asked the question: if we replace the gene that makes the enzyme that is missing in Leber’s Amaurosis, will this fix the disease? The next step was to find an animal model to test our theory. Fortunately, there was a disease in dogs that was exactly the same genetically as human Leber’s. The Lancelot study gave us the proof of principle we were looking for. The third step, going from animal models to human trials, is tightly controlled by International, Federal, and hospital internal review boards. Because of the huge expense of performing these strictly controlled studies, drug companies usually perform them. In our case, we very incredibly fortunate to be approached by A gene therapist at Children’s Hospital of Philadelphia, Dr. Kathy High. She asked us to partner with her group and CHOP agreed to back the effort along with the Foundation Fighting Blindness--- no drug company involved. The first phase of these studies is to extensively study the safety of the treatment.Our plan is to continue to maintain control for this part of the study.
The FDA has looked at the small number of people who have this disease and has granted an “orphan disease” designation. This means that the sample size of patients can be much less than the size needed for more widespread diseases, such as macular degeneration, diabetes or high blood pressure. Doing this type of study can cost upwards of $250,000 per patient. From a financial standpoint, the “orphan disease” status definitely helps in budgeting and ultimately getting to the point of FDA approval.

Editor: How far are you from a treatment?

Dr. Maguire: We feel positive about the benefits of our treatment. We feel we can complete FDA approval and have a treatment available to the public within 3 years. The thing that is most exciting is the technology that we have helped develop. This technology has never been used before. The same technology can be used to treat wet macular degeneration and diabetic retinopathy. Just imagine—you can treat a person once and their
eye will produce the product that will prevent new blood vessels from growing! This could eliminate the need for monthly eye injections and will hopefully eliminate the uncertainty of when to stop treatment. We have discovered a drug delivery system for almost any type of drug. We are excited to see what the future holds. Imagine if a Type I diabetic could produce (and regulate) his own insulin! The possibilities are limitless.

Editor: Our readers will be anxious to follow your progress. We look forward to speaking with you again. Thank you very much.

Note: Dr Maguire is a co-inventor on a patent for gene therapy for LCA, but has waived any financial interest.