Inside the Lab- with Lotje De Witte

By Dr. Dominique Pichard, Chief Science Officer, International Rett Syndrome Foundation

We at International Rett Syndrome Foundation keep the hope for Rett syndrome treatments alive in part by investing in research that translates the latest scientific concepts to Rett syndrome. This month’s Inside the Lab featured researcher, physician-scientist Dr. Lotje De Witte, is doing just that. We’re excited by her work’s potential to create new Rett syndrome treatment development opportunities and proud to share her innovative research approach with our community.

Dr. Lotje De Witte was actively seeking a genetic disorder where her lab’s unique expertise might benefit patients when she learned about Rett syndrome. It was the perfect fit, and De Witte decided to join the Rett research effort. Thanks to funding from IRSF, she is currently investigating how microglia, the brain’s immune cells, may play a role in Rett syndrome. Her work could reveal highly advantageous new avenues for treatment development.

“If there is something with the microglial cells, I believe it’s a good area to see whether we can modulate [it] with new treatment strategies,” De Witte states, “The immune system is very attractive because it is very responsive to changes in the environment, and we know already so much about how to change the immune system.”

Indeed, a variety of drugs that can either suppress unwanted or stimulate favorable immune cell activity already exist. As such, any novel Rett syndrome treatment approaches that stem from De Witte’s work could simply involve the repurposing of one of these established medicines rather than the time-consuming creation of a new one. De Witte’s research might also lead to new considerations for or insights into treatments currently in development. For example, it could help explain how the drug Trofenitide, which is known to affect microglia, may improve the symptoms of Rett syndrome.

Microglia in Rett syndrome
De Witte’s lab aims to enable these possibilities by defining the significance of the microglial abnormalities that have been detected in individuals with Rett syndrome.

Microglia provide the primary immune defenses for the brain, and science has shown that they are often activated by disease. Scientists currently suspect that this microglial activation impacts the brain. We know that the immune system influences the brain and vice versa. This brain-immune system connection explains some of the cognitive symptoms of illness such as difficulty concentrating, decreased appetite, and depressed mood that individuals experience during a bout of flu. However, we don’t fully understand how the immune system in general and microglia, in particular, change the brain in most diseases.

Rett syndrome is no exception in this regard. We don’t yet know if and how microglia contribute to the symptoms of Rett syndrome. However, relatively recent breakthroughs in microglia research provide some leads.

“There is a change in view about microglia that started roughly ten years ago,” De Witte explains, “[We now know that] microglia are not only the immune gatekeepers of the brain, but they are super important for neurodevelopment [brain development] and neurotransmission [communication between brain cells].”.

Specifically, microglia can act as the brain’s gardeners, shaping the brain’s communication pathways to function properly. This pruning function is essential in the developing and healthy adult brain. However, it could easily exacerbate problems with brain functioning in the context of a brain disorder such as Rett syndrome. For instance, over-pruning could contribute to the regression of skills in Rett syndrome and/or the persistence of symptoms in adulthood.

De Witte’s novel research design and connection with patients
De Witte’s research is distinct from the few other studies that have been performed on microglia in Rett syndrome in that it exclusively employs human-derived cells instead of mice. As one of the world’s leading experts on microglia, De Witte has access to cutting-edge human microglia models, including microglia integrated into brain organoids grown in Petri dishes. Additionally, she’s engaged Dalila Pinto, Ph.D., a fellow expert in brain disorders (including Rett-related disorders), as a collaborator to support this project.

Importantly, De Witte’s research design also creates opportunities for her to learn more about Rett syndrome directly from those affected by it. De Witte prizes these opportunities. She is looking forward to meeting individuals with Rett syndrome and their families.

“I want to get more involved with [doctors] that see the Rett patients and to hear what they are seeing,” De Witte says, “[This] will give you an insight into the patients themselves, and not only focusing on their [samples that we are collecting for this work].”

Throughout her career, she has found that interactions with patients often inspire the most ground-breaking research insights. Although the results of De Witte’s study won’t immediately impact individuals with Rett syndrome, such insights should help fast-track any directions for treatment development it provides. They will help keep the treatment development pipeline running and produce the next generation of potential therapeutics.

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