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Research inspired by NUCDF leader sheds light on mechanisms behind ASLD neurocognitive effects

Research image shows brain brain microvascular endothelial cells grown in a dish, stained with antibody to Claudin5

Cindy Le Mons, NUCDF's longtime executive director who passed away in 2022 (left, shown here with a patient), inspired research that is shedding light on the neurocognitive effects of certain urea cycle disorders.


Chasing down the role of nitric oxide in neurological dysfunction for patients with ASLD

Elevated blood ammonia levels are a classic symptom of most urea cycle disorders (UCDs) and can lead to neurological dysfunction. However, patients with arginosuccinate lyase deficiency (ASLD)—the second most common UCD—can experience neurocognitive impacts that go beyond what would be expected based solely on high ammonia levels. In some patients, the disorder can also lead to hypertension and liver disease.

What is causing these effects, and what could it mean for patients with ASLD and other UCDs?

Brendan Lee, M.D., Ph.D., of Baylor College of Medicine and his colleagues launched a line of research several years ago to answer those questions. Their latest paper points to an answer: the nitric oxide deficiencies common in ASLD create problems with the blood brain barrier, which is essential to maintaining brain health. Their work also highlights a potential path to treatments that may help more than just ASLD patients.

"I'm very proud to say that this paper was dedicated to 
Cindy Le Mons. She pushed us for many years to understand the neurological and brain issues in UCDs."

—Brendan Lee, M.D., Ph.D.

The work, he says, was inspired by Cindy Le Mons, the former executive director of NUCDF. “She pushed us for many years to understand the neurological and brain issues in UCDs,” says Dr. Lee. “I’m very proud to say that this paper was dedicated to Cindy.”

The blood brain barrier

Nitric oxide is a vasodilator. It relaxes the cells that line blood vessels, allowing blood, nutrients and oxygen to travel through the body efficiently. Since ASL is essential to the body’s ability to produce nitric oxide, patients with ASL deficiency can experience nitric oxide deficiencies.

The research team’s early research into the unique features of ASLD led them to first investigate the relationship between nitric oxide levels and hypertension (high blood pressure). In a 2018 study, they reported that patients with reduced nitric oxide levels caused by ASLD can experience endothelial dysfunction, a type of vascular disease in which blood vessels in the body can narrow.

Building on those insights, the team began exploring the impacts of nitric oxide deficiency on the blood brain barrier, a filter composed of cells that line the small blood vessels in the brain. This filter shields the brain from toxic substances and cells while bringing nutrients to brain tissues.

Through experimentation with both mouse models and human brain blood vessel cells, the team learned that deficiency of ASL and nitric oxide can cause leakage in the blood brain barrier.

“When the blood brain barrier breaks down, things that need to be kept inside the brain can leak out into the blood, and things that should be kept outside of the brain, can flow into the brain,” says Dr. Lee. “This breakdown can lead to all sorts of potential negative consequences, which we still don't completely understand. But we believe it could be one major driver of the neurological issues related to ASLD.”

The team also learned that claudin—a protein that regulates membrane permeability—likewise fluctuates with changes in nitric oxide and the blood brain barrier. These findings, Dr. Lee says, point to claudin-1 as a potential therapeutic target to reduce the neurological impacts of ASLD, along with nitric oxide supplementation.

Research images of brain blood vessels grown in a dish show that claudin (highlighted green), a protein that regulates the blood brain barrier, is dramatically lost with a deficiency of arginosuccinate lyase (right), compared to the image of control cells on the left.

Implications for patients, physicians

While not all ASLD patients have evidence of nitric oxide deficiency, some do.

“We have recommended treatment with nitrites when patients experience hypertension due to nitric oxide deficiency,” says Dr. Lee. “Now, we should potentially consider dietary nitrite supplementation to protect the blood brain barrier in patients with evidence of nitric oxide deficiency as well. It’s a reasonable conversation for patients to have with their doctors given the otherwise benign effects of these supplements.”

Further research into the impacts of high ammonia levels on the blood brain barrier may also open up new treatment options for other UCD patients, he says.

His team plans to continue research in this area as many questions remain to be answered. He also hopes this research will stimulate industry sponsors and other researchers to work to develop new treatments and conduct clinical trials.

Looking back, looking ahead

Dr. Lee and his colleagues are also setting their sights on future work in gene therapy. “Nitrite supplementation only attacks one element of the disease. We want to look at strategies to treat the ASL deficiency—and other UCDs—in all tissues,” he says.

He is excited about the potential of gene therapy, particularly recent advances in using messenger RNA as a delivery platform.

“I have been in rare disease research since day one of my career,” he says. “This field allows us to directly impact patients’ lives and offers an enormous ability for us to learn about nature and basic biology. For the patients, for our families, for science in general, it's a very powerful area in which to devote one's life.”

Cindy Le Mons, he said, played a huge role in helping to drive the field of rare disease research forward.

“I had the luxury of knowing Cindy since I was a new faculty and investigator studying UCDs,” says Dr. Lee. “She was such an inspiration to all of us. Not just because she was so smart, but also because she really knew the disease, via her own family experiences and all the families she helped. She was the perfect observational scientist, and her observations and intuition guided a whole field of scientists.”

“We all miss her very much, but her legacy will live on in the work that we do.”

Cindy Le Mons (front, center) with members of the Urea Cycle Disorders Consortium at a 2017 meeting. 

Read the full paper here, and follow all of Dr. Lee’s research here. Research into urea cycle disorders is supported by the Urea Cycle Disorders Consortium, part of the NIH-funded Rare Diseases Clinical Research Network

Citation: Kho J, Polak U, Jiang MM, Odom JD, Hunter JV, Ali SM, Burrage LC, Nagamani SC, Pautler RG, Thompson HP, Urayama A, Jin Z, Lee B. Argininosuccinate lyase deficiency causes blood-brain barrier disruption via nitric oxide-mediated dysregulation of claudin expression. JCI Insight. 2023 Sep 8;8(17):e168475. doi: 10.1172/jci.insight.168475. PMID: 37490345; PMCID: PMC10544197.

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