Home Cellular science Small amounts of carbon monoxide can help protect vision in diabetes

Small amounts of carbon monoxide can help protect vision in diabetes


04 November 2021 17:58 STI

Washington [US], Nov. 4 (ANI): An ingested fluid that ultimately delivers a small dose of carbon monoxide to the eye appears to target key factors that damage or destroy vision in type 1 and 2 diabetes, scientists say.
Scientists at the Medical College of Georgia have early evidence that HBI-002, a low-dose oral compound developed by Hillhurst Biopharmaceuticals and already in the early stages of trials for sickle cell anemia, can safely reduce oxidative stress and inflammation of the retina, both early, major contributors to diabetic retinopathy.
“Inflammation and oxidative stress go hand in hand,” says Dr Pamela Martin, cell biologist and biochemist in the Department of Biochemistry and Molecular Biology at MCG and at the Vision Discovery Institute at the University of Augusta. “If you impact one, you usually impact the other.”
In the right dose, carbon monoxide can impact both.
While we probably think of chirping detectors in our homes, toxic fumes from cars and trucks, and even death when we think of carbon monoxide, many of our own cells and tissues actively and regularly produce small amounts of carbon dioxide. colorless and odorless gas for protection. damage caused by high and / or chronic inflammation and oxidative stress, says Dr. Ravirajsinh Jadeja, MCG biochemist.
He talks about the enzyme heme oxygenase 1, a common component of many tissues, including oxygen-carrying hemoglobin and immune cells, whose jobs are to reduce oxidative stress and inflammation, and one of the ways to do this is to release small amounts of carbon monoxide. In fact, heme oxygenase 1 is naturally upregulated in our cells in response to increased levels of destructive states.
“Basically, the enzyme produces a very low amount of carbon monoxide, 1,000 times less than what we inhale on the outside,” says Jadeja. Unlike our homes where fuel ovens can cause high levels to build up, low and steady production and the cellular machinery that uses it also mean that the carbon monoxide we produce does not build up in our bodies.
“When you introduce diseases like diabetes, these natural mechanisms fail and we have to think of ways to improve or restore those mechanisms that would normally protect us,” Martin said.
Scientists have early evidence that HBI-002, a liquid that turns into a familiar gas when it hits our intestines, can help our retinas, which are damaged in almost half of people with diabetes, do so.
Martin and Jadeja are co-principal investigators on a $ 300,000 grant (1R41EY033264-01), for the first phase of an R41 / R42, Small Business Technology Transfer Grant from the National Institutes of Health which allows them to further explore the potential of HBI-002.
For the new studies, they are looking at the impact of the compound both in an acute ischemic model, when the retina suddenly does not receive enough oxygen due to oxidative stress followed by its normal inflammation, as well as in a disease model. more natural. progression.
The retina, which is considered an extension of the brain, is made up of complex layers of nerves that line the back of the eye and sense light, which the brain turns into images. The cell types in the retina are among the most metabolically active types of cells, which means they naturally generate a lot of oxidative stress, Martin explains.
One of his many long-term interests is to identify non-invasive methods of helping the retina, such as oral antihypertensives which help lower blood pressure.
Their preliminary studies indicate that HBI-002 can make the trip. The liquid transforms into the more familiar gaseous state of carbon monoxide in the intestines, where it naturally binds to hemoglobin – the component of the blood that carries oxygen – and then travels to the eye through the gut. blood, Jadeja said. Carbon monoxide is good for finding hemoglobin, scientists note. In fact, it’s its strong affinity for hemoglobin that makes it deadly, as oxygen can no longer bind to hemoglobin when carbon monoxide makes the link, Jadeja says.

“It’s bad, it’s deadly. When you hear carbon monoxide for the first time, it’s everyone’s reaction,” says Martin. “That’s true in a large, uncontrolled setting. But it’s in a very controlled setting where you get minimum concentrations that target specific cellular processes.”
Once in the retina, the small dose of carbon monoxide finds the enzyme heme oxygenase in the retinal cells and helps induce the steps that normally produce the desired antioxidant and anti-inflammatory action.
To objectively measure its impact, scientists have functional tests that – much like an EKG of the heart, but in this case an EKG – produce spikes and waves, which indicate how different cells fire up and signal. They can also examine the retina directly for telltale signs of damage: diabetes causes cell death and thinning of the retina, and can cause retinal detachment. RNA and protein analysis will provide more evidence of increased expression of good genes and decreased expression of problematic genes in response to treatment.
Meanwhile, levels of the carboxyhemoglobin complex, which forms inside red blood cells when hemoglobin is exposed to carbon monoxide and whose levels can be easily monitored with a blood test, are a good indicator of whether carbon monoxide levels remain safe.
HBI-002’s unique liquid-to-gas transformation allows for more targeted dosing as the amount needed can vary from individual to individual and, if ever approved for humans, will help ensure dosing accuracy. and the ability of patients to eventually use the compound easily and safely at home, say the scientists and its developers.
It also leaves nothing behind, while a previously studied pill form left behind metal complexes that needed to be cleared by the kidneys, which are also often compromised in people with diabetes, Jadeja says.
If the evidence for the benefits of HB1-002 continues to hold up in their studies over the next 12 months, this will lead to another grant and further studies on how this carbon monoxide compound works against the ravages of diabetic retinopathy, exploring optimal doses, how many times it should be given and more.
While they and other scientists studying the compound have reported no side effects, the sickle cell trial just started should provide more information. Martin notes that they expect to see minimal impact, if any.
Earlier this year, the United States Food and Drug Administration cleared Hillhurst to go ahead with a first-phase trial of its HBI-002 for sickle cell disease. Phase 1 trials are intended to test safety and are performed on healthy individuals. The company has preclinical evidence that the compound will prevent classic pain attacks that occur when adequate blood flow is disrupted by sickle red blood cells in the arms, legs, bones, joints and other tissues.
While the causes of sickle cell anemia and diabetes can be disparate, they share common players like oxidative stress and inflammation, Martin notes.
“While we are generating this data, they will continue this trial,” Jadeja said. “We are working on something that is very close to clinical use.”
The back of the eye has been a difficult target for drugs. For example, using eye drops as a delivery mechanism is usually not effective because often the drug does not reach the retina, and if you give enough doses to help it make the trip, it can cause damage. the front of the eye, says Martin. So, diabetic retinopathy therapies tend to be invasive, such as intravitreal injections of drugs that help reduce the abnormal and destructive growth of blood vessels that occurs in response to blockage of existing blood vessels but ultimately contributes to the loss. of vision.
According to the American Diabetes Association, diabetic retinopathy is the most common cause of new cases of blindness in 20-74 year olds and is strongly related to the duration of diabetes.
Carbon monoxide has also been shown to play an important and natural role in dilating blood vessels and repairing cell powerhouses called mitochondria, scientists say.
Hillhurst Biopharmaceuticals is a clinical stage company focused on blood and inflammatory disorders. Preclinical studies of their HBI-002, like the ones Martin and Jadeja are conducting in diabetic retinopathy, are also underway in conditions such as Parkinson’s disease and acute pain. (ANI)