MIAMI, Fla. (Ivanhoe Newswire) - It can rob you of your sight before you even know there's a problem. In its most common form, glaucoma has virtually no symptoms and there's no cure, but a new trial is helping patients attack the condition non-stop.
"I built [my] house back in '71," Kenneth Smith told Ivanhoe.
Now in his seventies, Kenneth Smith just renovated a bathroom and he's working on another, all while learning the banjo. But one thing threatens to put an end to Kenneth's active lifestyle.
"Glaucoma," Kenneth said.
Now, he's enrolled in a unique trial at Bascom Palmer Eye Institute.
"It turns out glaucoma is a neurodegenerative disease," Jeffrey Goldberg, M.D, an associate professor of ophthalmology at Bascom Palmer Eye Institute at the University of Miami, explained.
Doctor Jeffrey Goldberg said vision cells degenerate during glaucoma just like brain cells do in Alzheimer's and Parkinson's. While standard glaucoma therapies focus on the front of the eye and eye pressure, he's looking at the back of the eye and its connections to the brain. He believes a molecule called CNTF could be key to a breakthrough.
"It's expressed all through the eye and the brain," Dr. Goldberg said.
To stop the progression of glaucoma and maybe even restore vision, he's testing this device to boost CNTF in patients.
"It saves us from having to inject the CNTF into the patient's eyes over and over and over again," Dr. Goldberg said.
The implant is put in the white of the eye and contains engineered cells.
"And they make the CNTF constantly and pump it into the eye," Dr. Goldberg said.
It's been months since Kenneth got his implant and things are looking good.
"Yes, I'm seeing better," Kenneth said. "It's still not 100 percent like I would like it to be. [I'm] Looking forward to getting better and better."
Doctor Goldberg said so far patients in the trial haven't seen any major side effects from the implant. He said the procedure takes about 15 minutes and the implant starts working right away. He believes it could deliver the possible vision saving molecule directly to the eye for a year or more.
BACKGROUND: Glaucoma is a complicated disease where damage to the optic nerve leads to progressive, irreversible vision loss. It is the second most common cause of blindness in the United States. Everyone is at risk for glaucoma, there may be no symptoms to warn you, and there is no cure for the disease. It is estimated that over 2.2 million Americans have glaucoma but only half of those know they have it. (Source: Glaucoma Research Foundation)
TYPES: There are four major types of glaucoma:
Open-angle (chronic) glaucoma –An increase in eye pressure occurs slowly over time. The pressure pushes on the optic nerve. Unknown cause, tends to run in families
Angle-closure (acute) glaucoma- occurs when the exit of the aqueous humor fluid is suddenly blocked. This causes a quick, severe, and painful rise in the pressure in the eye. This is an emergency, and if you have had acute glaucoma in one eye, you are at risk for an attack in the second eye.
Congenital glaucoma- seen in babies and present at birth due to abnormal eye development.
Secondary glaucoma- caused by drugs like corticosteroids, eye diseases, systemic diseases, or trauma. (Source: www.ncbi.nlm.nih.gov)
TREATMENT: A dilated eye exam is the best and most effective way to detect glaucoma. Treatment can't cure glaucoma, but it can prevent and avoid further vision loss. Different treatments for glaucoma include medicated eye drops, oral medications (usually a carbonic anhydrase inhibitor), Drugs that protect the optic nerve, and surgery to lower eye pressure. Advocates of medicinal marijuana cite evidence that hemp products can lower intraocular pressure (IOP) in people with glaucoma. However, these products are less effective than medicines prescribed by an eye doctor. Additionally, side effects of long term use of marijuana can override any potential benefits. (Source: Mayo Clinic, Glaucoma Research Foundation)
NEW TECHNOLOGY: Neurotech's product, NT-501, contains encapsulated human cells genetically modified to secrete ciliary neurotrophic factor (CNTF). CNTF is a growth factor that is able to rescuing dying photoreceptors and protect them from degeneration. NT-501 is designed to continually deliver a low, safe and therapeutic dose of CNTF into the back of the eye, and is designed for the potential treatment of retinitis pigmentosa (RP) and age-related macular degeneration (AMD). (Source: Neurotech)
Dr. Jeffrey Goldberg, associate professor of ophthalmology at Bascom Palmer Eye Institute at University of Miami, talks about a new approach that could reverse vision loss.
Tell us about this trial. It seems pretty exciting to slow down or even restore vision for people that have glaucoma.
Dr. Goldberg: Absolutely. We are very excited about it. The treatments in glaucoma have really focused on treating intraocular pressure, or eye pressures. We know that for most patients if we can lower their pressures with medicines or with surgery, we can slow or in some cases, maybe even halt the progression of the disease. But certainly, we have some patients for whom lowering the eye pressure is not enough, or they cannot tolerate all of the eye drops, or the surgeries do not work for them. We also have some patients whom we just catch too late in the disease and they have already lost significant vision. For these groups of patients in particular, we really want to find new treatments, new ways that we can prevent vision loss or even bring back vision that they have lost, which traditionally we have not been able to do in glaucoma. There have been a number of new treatment ideas, approaches, drugs that have been tested, and look like they work really well when we look in preclinical models, but transitioning those to clinical trials has proven challenging. We have started a trial here taking advantage of one of these drugs, a molecule called ciliary neurotrophic factor or CNTF. It turns out that it is expressed all through the eye and the brain, but we might argue not in high enough amounts. A company in Rhode Island, Neurotech, devised a way to deliver it inside the eye using a little implant, and we have been testing this now in patients with glaucoma.
And this study also takes an interesting turn looking at glaucoma as not just an eye problem, but a neurological problem as well, correct?
Dr. Goldberg: Absolutely.
Why are you taking that approach?
Dr. Goldberg: Glaucoma is a neurodegenerative disease. The focus has, of course, been on really the front of the eye where eye pressure is controlled, so all of the treatments so far have focused on the front of the eye. But the loss of vision occurs because we lose the fibers that connect the eye to the brain in the optic nerve, and that is really the only highway carrying visual information from the eye to the brain. Those fibers are called "axons" and they are attached to neurons or cells in the retina that are collecting all of the information about the visual world. Those retinal cells are called "retinal ganglion cells." The retinal ganglion cells degenerate in glaucoma just like other very specific cells in the brain or spinal cord degenerate in other neurologic disease like Lou Gehrig's disease or Parkinson's disease or Alzheimer's disease. Not only that, we have begun to appreciate that the neurodegeneration that happens in glaucoma bears a lot of similarities to the neurodegeneration that happens in these other degenerative diseases. There is a loss of connectivity from cell to cell. The neurons stop talking to each other. There is some sort of injurious process which for glaucoma, we still do not really understand. Then we have a slow degeneration, a slow loss of these cells where they dysfunction initially and then eventually die. So thinking about the disease in this way has allowed us to open our minds to new treatments. Treatments that are not just about eye pressure, but may also be about protecting these cells from dying or protecting the fibers from dying or even encouraging these fibers to regrow or regenerate back through the optic nerve and reconnect back to their targets in the brain.
How does CNTF do that?
Dr. Goldberg: CNTF is a protein that is expressed normally in the visual system and it is a called a trophic factor. It normally signals survival and growth of retinal ganglion cells and their axons. It has been long demonstrated in a variety of preclinical models that if you have an injured optic nerve and you give extra CNTF, usually just by injecting it into the eye, that you can increase the survival of retinal ganglion cells and also encourage their axons, those fibers in the optic nerve, to regrow back towards the brain. CNTF gets bound and taken up by the retinal ganglion cells and perhaps by some of the neighboring cells around them that help feed the retinal ganglion cells all the good things that they need to survive and grow. It sets off a signaling pathway inside the retinal ganglion cells that encourages their growth.
How does it know when to release some CNTF?
Dr. Goldberg: This particular delivery system is really ingenious. It saves us having to inject the CNTF into patient's eyes over and over and over again over the course of months or years. The delivery system is a small capsule. We insert it through the white part of the eye, called the sclera, into the jelly in the center of the eye, called the vitreous, where it stays inside. Inside of this little capsule, there are little human cells, not stem cells but similar, a "cell line," and the cells have been engineered to express CNTF. They make the CNTF constantly and pump it into the eye. By implanting this little capsule, patients are actually getting exposed to a low level of CNTF over a long-term; certainly we think over months and perhaps years. Now, we do not know if it is enough CNTF. We do not know if it is enough to have a positive effect, we are just taking the early steps towards eventually testing whether it is effective in this and other diseases, but it still is laying for us a model for how to move forward translating what we have learned in preclinical models into patient trials.
What did you see in preclinical trials?
Dr. Goldberg: Preclinical trials have been really remarkable. Much of the work has been done in rats or mice, although sometimes larger animal models have been tested. In these various models, if you injure the optic nerve, whether by increasing the eye pressure as would happen in glaucoma or even physically damaging the optic nerve, normally the retinal ganglion cells first of all fail to regrow their axons past that injury site in the optic nerve. Then shortly after, the retinal ganglion cells start to die. And, what we have seen in countless preclinical models performed in our lab and many other labs around the country and around the world is that CNTF can slow that death or prevent some of those cells from dying. Furthermore where normally there is no axon regeneration into the optic nerve, with CNTF there is regeneration into the optic nerve.
Have you seen anything like that before where you see the regeneration?
Dr. Goldberg: There are other drugs, other treatments as well, that are effective in promoting regeneration. The nice thing about CNTF is that we are able to take advantage of the fact that it had already been prepared for human trials in macular degeneration for insertion into the eye. We were able to take advantage of the fact that this CNTF was ready for testing in human glaucoma and in human optic nerve diseases like optic nerve stroke. There are other treatments that other companies and academic centers are bringing to clinical trial as well. It is going to be exciting over these next few years to start testing those too, finally, in human patients.
Have you seen any kind of response from anyone who has taken part in these trials?
Dr. Goldberg: In the CNTF trial for glaucoma and also for optic nerve stroke, we are between one month and 7 months post implantation right now. So far, we have not seen any serious adverse events, which is really the main goal of these phase 1 trials. No one in our trials is getting a placebo or a fake implant into the eye. They are all getting the real thing. That is, of course, nice for the patients who are motivated to try the real thing, but it is a challenge for us scientifically because we cannot compare the patients who are getting the implant to the patients who are getting a fake implant. Because we cannot do that comparison, we cannot say anything statistically speaking about whether it is having a positive effect. What we can say, again, is that it appears to be safe in this group of patients and we are having a small inkling that at least some patients are feeling like they are seeing better. But, it is really too early to say.
How long will this first phase go? What was your outline for that?
Dr. Goldberg: The first phase trial is going to be an 18 month trial. We will of course be analyzing data along the way to see if things look promising and to make sure everything looks safe. Of course after 18 months, we will continue to follow these patients for as long as they will let us. But, formally, it is an 18 month trial. If things look positive after 18 months, we will hope to move forward into later phase trials. That, of course, will be a big discussion both amongst the investigators and with the company that makes the implant.
What is your hope with this?
Dr. Goldberg: My hope is that either with this medicine or perhaps with other medicines that are being developed and move into human trials, we will develop something for patients that really helps them bring back vision, really helps protect them from vision loss; gives us another avenue for treatment other than controlling the pressure to prevent vision loss in glaucoma. I think that if we have two different approaches to prevent vision loss or to restore vision perhaps, that would obviously be twice as good for patients.
How are the fibers and the eye pressure are tied together?
Dr. Goldberg: Treating the eye pressure and treating the underlying susceptibility to high pressure that happens in glaucoma patients, that cell death and lack of regeneration; are likely completely independent. A nice feature about developing a second approach, in this case, a neuroprotective or regenerative approach, that is completely independent of eye pressure, is that patients could be treated with both approaches and improve the chances that they do better in their disease. In a way, what we would like to do is make at least some portion of glaucoma independent of pressure so that if patients have trouble tolerating their pressure eye drops, maybe they are protected by this second approach.
You see that new approach being able to prevent the eye pressure at some point?
Dr. Goldberg: Treating the retinal ganglion cells and the optic nerve through this or another approach would be a great step forward in preventing the cell death and maybe make the optic nerve damage progress more slowly or even regenerate, but it would be completely independent of eye pressure. In fact, it would be a wonderful thing if through one of these treatments, patients were no longer sensitive to high eye pressures and we did not even have to worry as much about controlling the pressure. Of course, we want to make sure that none of the treatments that we give to the back of the eye or the optic nerve themselves increase eye pressure because that could be very bad for glaucoma patients.
Is it just a quick injection of the device?
Dr. Goldberg: This particular device is inserted through the white part of the eye, the sclera. It is a very short surgical procedure. To be safe, we do it up in the main operating room with the patient getting full anesthesia. There is no pain from the procedure. It takes about 15 minutes to insert and then we sew up the eye and the patient heals over the course of a few weeks or a month as the sutures absorb and disappear.
Does it start working right away once it is injected?
Dr. Goldberg: It does. In fact, we have to be careful when we are putting it into the eye, that we put it in very quickly. We do not want it to dry out on the way. Otherwise, it might not work as well. But, it does start working right away. We think from all of the data that has come before that it should continue to make the CNTF inside patient's eyes on the scale of a year or many years.
That sounds promising. Exciting.
Dr. Goldberg: It is very exciting just to be a part of testing. Even if we do not know if it is going to work, I think that patients are really eager, especially patients who have lost vision are eager for new approaches for regenerative therapies. Just to start moving these and translating them from the laboratory into the clinic, I think is an important step that we all want to take in academic medicine.
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