Dr. Mark Petrash is Professor and Vice Chair of Research in the Department of Ophthalmology at the Rocky Mountain Lions Eye Institute at the University of Colorado Denver and is a leader in the field of aldose reductase research. Never heard of aldose reductase? Here’s a primer: Aldose reductase is the enzyme that converts glucose to sorbitol. Aldose reductase activity increases in the body as the glucose concentration rises, so in diabetics with high blood sugar levels, more and more sorbitol gets produced. Sorbitol, while good in small amounts, is bad when overproduced and contributes to many of the complications of diabetes, especially kidney disease (nephropathy), nerve pain (neuropathy), and loss of vision (retinopathy). For more on aldose reductase and sorbitol see here.
A drug that inhibits aldose reductase activity can prevent the increase in sorbitol production experienced by so many diabetes patients, and thereby prevent diabetic complications. Unfortunately, the drugs currently available to inhibit aldose reductase have many side effects. Medical research is continuing the search for effective aldose reductase inhibitors, and Dr. Petrash is one of the leaders in this area. He took the time to sit down with Robert Scheinman for ASweetLife and explain why this drug class is so difficult to develop, and why it holds such great promise.
Dr. Petrash, thank you for taking the time to talk with ASweetLife. As you know we do not yet have an aldose reductase inhibitor available in the United States. How do you think the aldose reductase inhibitors stack up in comparison to other diabetes therapies? Do you think that they are going to make a difference?
I think that they are very promising – especially in the context of retinopathy (retinopathy is the progressive loss of vision experienced by many diabetics that can ultimately lead to blindness). Currently, we don’t have any kind of drug that’s effective at blocking retinopathy. Quite a number of other pathways have been targeted but none have been successful in the clinic. If you are going to target a pathway with a drug your hope is that when you block with the drug there wouldn’t be side effects. One way for side effects to occur is if the pathway is used for more than one function. We have studied mutant mice where the aldose reductase gene has been deleted, and as far as we can tell there are no ocular side effects when the activity of this enzyme is completely removed.
Tell us about the history of aldose reductase inhibitors in clinical trials.
The first aldose reductase inhibitor to undergo a large clinical trial was Sorbinil. It could reach the target tissues of diabetes but was associated with side effects that made it unacceptable including allergic reactions and liver toxicities. Because of these complications, the study had to be terminated. Subsequent drugs which had better inhibitor properties were not successful because they simply did not penetrate target tissues such as nerves, and the eye– and some of them were associated with liver toxicity (Aldose reductase inhibitors that can penetrate nerves will treat neuropathy and likewise, those that penetrate the eye to reach the retina will treat retinopathy).
There is an aldose reductase inhibitor currently being marketed in Japan. Is this one of the drugs you just mentioned or a different one?
That is correct. Epalrestat is marketed in Japan and appears to be well tolerated in patients. There have been reports that this drug helps to alleviate some of the painful neuropathy associated with diabetes, but I am not aware of large studies that have been completed to assess its efficacy against diabetic retinopathy.
How are you addressing this problem?
We are taking the approach that by paying attention to other cultural practices we may find new aldose reductase inhibitors. For example, in India there are certain plants that seem to have properties that provide protection from diabetes and diabetic complications. One of these plants is called amla or gooseberry. In collaboration with Dr. Bhanu Reddy at the Nutrition Institute of Nutrition in Hyderabad, India, we have published some papers showing that materials in gooseberry fruit will delay the onset and the severity of cataract formation in a diabetic rat model. We are now working to isolate and study compounds from this plant that we think can confer this therapeutic benefit.
Our goal is first to see if we can understand the chemical nature of the therapeutic compound so that we can- first of all- test the concept that this is working by a mechanism that we can understand, and then, by deciphering the chemical makeup of these therapeutic compounds we can study ways to enhance the uptake of these compounds by tissues. One of the challenges is getting an orally administered drug from the blood to the brain and the retina. We are collaborating with Dr. Daniel Labarbera here in the School of Pharmacy at the University of Colorado to study the chemical composition of these natural inhibitors as a first step in determining whether they may be useful as therapeutic agents.
How did you find out about this plant?
We have been collaborating with Dr. Reddy for many years. Fortunately, the health effects of this plant are very well known in the practice of Ayurvedic healing in India. In fact, I was just in India a few months ago. While speaking with a scientist who was not a vision scientist and who did not work on diabetes, I explained to him that we were studying the amla fruit. His response was “Of course. My grandmother always had us spread amla jelly on out toast because it was good for your health and it prevents diabetes!”
Curcumin is another spice that is used in Indian cooking. We just published a paper with Dr. Reddy’s lab, showing that that curcumin, which is known to protect against certain diabetic complications, is also a very potent and selective inhibitor of aldose reductase.
Should we start thinking about bringing amla jelly to the United States? Will it actually be of clinical benefit to people at risk of developing diabetes or diabetic complications?
I think it is too early to tell. I will say, however, that many Indian groceries carry it in the United States. It is so common in Indian culture that it is imported over here. I personally enjoy Indian cuisine, so I visit my local Indian grocery quite often.
When in the course of diabetes do you envision aldose reductase inhibitors having the most benefit?
I would see aldose reductase inhibitors as prophylactic drugs—that is, preventative drugs. Our goal is to develop inhibitors that can be used not just to treat existing retinopathy, but also to prevent the onset and progression of retinopathy in the future. There are very powerful new drugs available to control the neovascular growth in the late stages of retinopathy. These are called vascular endothelial growth factor inhibitors, such as Lucentis. (After the initial damage to the retina occurs, the body tries to heal by growing new blood vessels. This is called neovascularization. Unfortunately, the process only makes things worse and propels the patient from vision loss to blindness. Blocking neovascularization at this stage allows patients to retain some vision).
VEGF inhibitors are very good at reducing the fragility of the neovascular vessels that grow in the retina, but please understand that this occurs as one of the late stages of advanced retinopathy. A lot of bad things have happened to the retina before it starts developing neovascular growth. Our goal is to prevent those bad things from happening in the first place. We think that targeting aldose reductase is a good strategy if it can be initiated soon after diagnosis with a highly specific compound that is capable of penetrating the eye. This way we can shut down the process of retinopathy before it gets started rather than treat the devastating after effects.
The treatments that ophthalmologists currently use to control retinopathy cause destruction of retinal cells and blood vessels. This procedure obviously can be done only so many times because the cells cannot replace themselves after treatment. The treatment uses lasers to kill cells in the eye. The ophthalmologists have to be careful that these lasers do not affect the macula – the most sensitive region of the eye. Yet, at the same time they are destroying the tissues that we use to see. I think that we are smarter than that and that we need to develop therapeutic strategies to block the disease before the damage occurs, rather than use lasers to mitigate the damage.
While our focus is on retinopathy, there’s one other thing I might mention: we know that diabetes has an effect on the kidney and on peripheral nerves in the body. There is also very solid evidence that aldose reductase plays some role in diabetic neuropathy and diabetic nephropathy. So we believe that discovering and optimizing new aldose reductase inhibitors for retinopathy will have a spinoff effect and potentially be useful against diabetic neuropathy and nephropathy as well.