Fernando Scaglia, MD, Professor of Genetics at Baylor College of Medicine talks about a new trial that looks to combat the stroke-like episodes associated with MELAS syndrome.
Interview conducted by Ivanhoe Broadcast News in January 2022.
Talk to me about I believe it’s called MELAS syndrome. What is it?
DR SCAGLIA: MELAS syndrome is a condition or a disorder of energy metabolism. When people ask me what do you do for a living? I say, I’m an energy specialist, and they think that I’m in the oil and gas field. However, I would say no. I’m in the cellular energy field and therefore I see patients with mitochondrial disorders. Mitochondria are the energy factories of the cell. They produce the energy or ATP that our cells and tissues use to carry out their tasks. When there are either changes in the mitochondrial genome, mitochondrial DNA or in the nuclear genome or nuclear DNA that affect the function of the mitochondria, then problems associated with this low energy occur. Specifically, MELAS is an acronym and stands for mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. In plain English that means that children and adults have problems with the functioning of their muscles and brain and they also have high lactic acid levels. Lactic acid is produced when the mitochondria do not produce enough ATP, and then sugar must be broken down to produce ATP. It is not a very efficient way of generating the energy currency of the cells or ATP. Finally, the last letter of that acronym is stroke or what we call metabolic strokes. And these strokes can be quite debilitating in this condition.
How common is it for someone to have this?
DR SCAGLIA: Approximately between one in 4000 and one in 5000 individuals in the United States has a mitochondrial disease. Among this group of disorders, MELAS is by far one of the most common disorders. Although the initial studies or population studies were done in Finland and Japan, at Baylor College of Medicine and Texas Children’s Hospital we are doing a study funded by NIH to see how common, how frequent mitochondrial disorders are and how frequent MELAS is. This study is part of a registry of patients, children and adults funded by the National Institute of Health.
I never heard about it until I ran across it on here. So, with the condition itself, you mentioned a little bit about the symptoms, but can you go into like what causes someone to have it? What are the risk factors?
DR SCAGLIA: In the case of MELAS, 80% of patients have what we would call a common genetic letter change in their mitochondrial DNA, and that will affect the way mitochondria manufacture proteins, what we would call mitochondrial protein synthesis. We all rely on proteins to live, to carry out our lives. If mitochondria do not function well, they will also produce toxic compounds called free radicals which would even cause further damage, and this will all lead to a lack of energy. This lack of energy or this lack of ATP will affect organs that are more susceptible to a lack of energy like the brain and therefore we would have the stroke-like episodes. There could be patients with MELAS who could have seizures, fatigue, and muscle weakness among several problems. The heart can also be affected. So, several organs can be the target of this genetic problem.
Is someone typically born with it or is it something that occurs along the way that develops?
DR SCAGLIA: A person is born with a genetic letter change but will probably not present this syndrome at birth. Most patients will present and there is an age range. The age range goes from 2 years to 40 years. The timing for the presentation will also depend on the load of the genetic change or mutation, in other words the percentage of the mutation. The higher the load of the mutation, the earlier the person will present, and maybe even more organs will be involved or will be compromised.
Talk to me a little about your trial. Tell me what’s happening. What are you having the patients do?
DR SCAGLIA: We’ve done a previous pilot study at Baylor College of Medicine and Texas Children’s Hospital. In those previous pilot studies connected with the trial, we found out that there is a deficiency of a compound. It’s like a chemical compound in the body. It’s called nitric oxide. We thought that this deficiency of nitric oxide could lead to the incidence of metabolic strokes. This deficiency was only found in the patients with this syndrome and not in healthy participants. The patients participating in this pilot study received two building blocks of proteins, two amino acids, arginine and citrulline and both restored the production of nitric oxide. Then, we noticed that citrulline was more efficient than arginine and therefore we received funding from the National Institute of Health through this mitochondrial consortia called NAMDC that is also funding the registry of patients with mitochondrial disease to do a safety study, a phase one study, to look at the safety profile of citrulline. So, we are trying to find the maximum tolerated dose of citrulline in adult patients with MELAS having this particular genetic letter change. They must have it and they have to have at least one previous episode of a stroke.
I know the trial is still in early stages, but has there been any results that you have found so far?
DR SCAGLIA: No. It’s too early since we just started. We were going to start in 2020 and obviously the clinical research unit was closed because of the COVID-19 pandemic. So, we were only able to restart the trial in end of April, beginning of May of 2021 and we have just enrolled our patient number five who into the trial. The trial lasts for two months and again focuses on the safety of this compound called L-citrulline, which is an amino acid and there is one additional patient who has expressed interest in coming to the trial. We are hoping to enroll a total of 24 patients in this trial.
For the trial, you touched on it a little bit, but are you changing the dose for the patients as they go along or is it different groups will have?
DR SCAGLIA: That’s a very good question. The dose is being changed and we are collaborating with a statistical group. There is a group of research statisticians who are collaborating with us from there are funded by the mitochondrial registry by NAMDC and by NIH and we communicate with them. The idea would be that if the first dose is tolerated, then in the next patient, the dose would be escalated, would be increased. That would be determined by the statistical team. So, yes. The idea would be that in each patient the dose would be different if it has been tolerated in the previous patient but that will ultimately depend on the feedback received from statistical group.
So, the very first patient, he probably had the lowest dose?
DR SCAGLIA: He had the lowest dose of citrulline, yes.
What happens for patients that have MELAS if they don’t get this condition treated? What will happen?
DR SCAGLIA: They are at risk. It depends on the mutation load. Obviously, we are targeting a population of patients with MELAS who have strokes, who at least have like one previous stroke episode. There are patients with MELAS who have I guess lower amount of the change, of the genetic letter change, who only have short stature and hearing loss. There are other patients who have hearing loss and diabetes, but this case it’s strokes. Now, obviously, if the strokes are left untreated and we don’t trial new approaches or new experimental medications, there’s always a risk that a person could have – a patient could have progressive decline with several strokes. And there’s also cognitive decline. Unfortunately, as the strokes occur, they would also have dementia.
Could you go into a little bit more on the symptoms itself? You mentioned the stroke-like episodes, the hearing loss, what are the symptoms of MELAS?
DR SCAGLIA: So, the symptoms are broad. The symptoms also will depend on the level or the amount of the mutation in different tissues. At the milder end of the spectrum, people may have, or patients may have short stature and then they will have hearing loss. Maybe at higher levels they are going to have diabetes. All of these patients will experience fatigue due to the lack of cellular energy. They are not going to be able to exercise or if they walk for a certain period, they will feel very tired, wiped out and then at higher levels of the mutations, they could have these problems with strokes. Other patients may have seizures. In some cases, the seizure itself, the seizure episode may be a manifestation of a stroke, of a metabolic stroke. There are other patients who may not necessarily have metabolic strokes but may have kidney disease. Some of them may end up having renal failure, end stage renal disease and they may rely on dialysis. The symptoms are very broad and very diverse. It’s not just the strokes. We are targeting that population because we think based on pilot studies that were done at Texas Children’s Hospital and Baylor College of Medicine, that the deficiency of this chemical, this compound nitric oxide, may be responsible for the strokes. We are trying to find out at this stage whether by giving an amino acid that would restore the level of nitric oxide, whether first it would be safe. So, this is sort of like the safety part of the study, but then we have to conduct other studies and looking at the efficacy of citrulline.
Since the symptoms are so broad, is there a chance that someone could get misdiagnosed with something else when it’s really MELAS?
DR SCAGLIA: There is a concern that may happen, and I think that that’s a concern for maybe all types of mitochondrial disease, that if doctors or health care personnel are not aware of these conditions, that they may be misdiagnosed or mislabeled and confused with other conditions or that they may be diagnosed late. Typically, these are conditions or patients that are going to present to obviously if they have strokes to a neurologist, to adult neurologist, and in some cases to geneticists.
What are some current treatments right now for the condition?
DR SCAGLIA: Well, so MELAS and most of the mitochondrial disorders, the conditions are orphan disorders, and the treatments so far have no proven efficacy. So, in many cases, many specialists may use antioxidants but that may rely more on anecdotal evidence rather than randomized clinical trials which should really be the gold standard. And there are – I mean, there are in some cases, there were previous observations in Japan that another amino acid called arginine could be used chronically in patients with MELAS to try to prevent strokes. However, that was not assessed as part of a clinical trial. So, that’s why we are doing this study.
I know you’re on the early stages now, but once you get those 24 patients and you have the data, what are you hoping to get out of this?
DR SCAGLIA: First, that the use of citrulline is safe and we also have other outcome measures. We are doing a special type of research brain MRI, that is being done at a facility at Baylor College of Medicine called CAMRI, and we are looking at the baseline. So, when the patient first comes, the patient is not on citrulline yet, and then we are doing that a month after while the patient is still on citrulline. Then we are comparing and seeing whether there is any difference in the way the blood vessels in the brain react, because we think that the strokes are not necessarily connected with problems in the large blood vessels in the brain as we typically think of a stroke, that either there would be like a bleeding or a clot causing that. We think that there are problems in the tiny blood vessels that may be more susceptible to the lack of nitric oxide. So, we are also looking at that to see if, you know, we are able to impact on the blood flow in the brain, but then this should be followed by another segment, by another trial that would really look at efficacy. So, we are looking at eventually doing a long-term efficacy study. This is really like a short-term two-month study. We are looking at the long term and probably like recruiting more participants and eventually do a multicenter trial. This trial right now, although, you know, funded by NIH, is being conducted at the Clinical Research Center at the Baylor Clinic at the McNair campus. Therefore, this is a single site trial.
Anything I didn’t ask you that you feel that people should know?
DR SCAGLIA: I think participation in clinical trials is key and it’s really key to really provide answers to patients and families with these disorders. These are like rare disorders. I think that it’s difficult to recruit patients for rare disorders because the numbers are not as large as for other conditions. I think that that’s why a clinical trial is key because it really moves us beyond anecdotal reports. If we rely on providing medications based on anecdotes, it’s really a disservice to the community and it’s a disservice to patients and their families.
END OF INTERVIEW
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