New breakthrough: experimental cancer drug shows promise in reversing cognitive decline in Rett syndrome

University of California San Diego researchers suggest that an experimental cancer drug may enhance cognitive function in individuals with Rett syndrome, a rare condition linked to Autism Spectrum Disorder (ASD). This breakthrough could pave the way for treatments targeting neurological disorders.

Mesci et al initially published a study on July 25 2024 in Stem Cell Reports,  underscoring the importance of microglia, a type of white blood cell in the central nervous system, in brain development. While microglia have been extensively studied in neurodegenerative diseases like Alzheimer’s, ALS, and multiple sclerosis, their role in early brain development has remained largely unexplored due to limited access to fetal tissue, as explained by Dr. Pinar Mesci. To overcome this challenge, Mesci used brain organoids, or ‘mini brains’, derived from the skin stem cells of consenting patients. These organoids were created from both individuals with Rett syndrome – a condition mainly affecting females and characterised by the loss of speech, motor skills, and muscle tone, and neurotypical individuals.

Microglial cells in neurodevelopment have only recently come into the spotlight, with a previous static vision of their role in healthy human brain development. Researchers have found that microglia, a type of brain cell usually involved in the immune system, also play a key role in brain development, particularly in forming connections between neurons. In a recent study, scientists used genetically modified mice with a defective MECP2 gene to show that microglia are important for creating these connections.

They also discovered a drug, ADH-503, that can help restore these connections, showing promise for treating conditions like Rett syndrome

Additionally, scientists created lab-grown microglia-like cells from stem cells and found that they closely mimic real human microglia. This breakthrough means these cells could be used to study brain disorders, such as autism. The research also showed that when microglia are affected by a defective MECP2 gene, they do not function properly, leading to problems in the brain. ADH-503 improved microglia function in lab experiments and mice, offering hope for new treatments for conditions linked to MECP2 gene defects

To ensure that the drug is ready for the market, many further developments are needed. The study results are promising, but extensive clinical trials are necessary to determine the safety and efficacy of ADH-503 in humans. These trials would need to include various phases, from initial safety assessments to broader efficacy studies in larger patient populations. Even with successful trials, obtaining regulatory approval from agencies is crucial. This requires demonstrating that the drug is safe, effective, and produces a consistent therapeutic effect. Scaling up the production of ADH-503 and ensuring consistent quality across production is essential.

Also, a distribution plan is necessary, including considerations for pricing, accessibility, and patient education. While the study focuses on Rett syndrome, further research is needed to explore the drug’s efficacy in other neurological disorders.

Understanding the broader implications of MECP2 and microglial dysfunctions could reveal additional therapeutic applications

The need for new treatments like ADH-503 arises because existing treatment options for  Rett syndrome, are limited. This study demonstrates that Rett syndrome is caused by mutations in the MECP2 gene, which leads to problems in brain development and function. Current treatments mostly focus on managing symptoms, such as physical therapy, medications for seizures, and support for breathing difficulties, rather than addressing the root cause of the disorder. One major challenge is that traditional treatments do not target the underlying genetic and cellular dysfunctions caused by MECP2 mutations. ADH-503 addresses one of these critical issues: the dysfunction of microglia, brain cells that help maintain healthy neural connections. By improving microglial function, ADH-503 has the potential to slow disease progression and improve brain health, which current treatments do not achieve. While current therapies help manage symptoms, there is no cure for Rett syndrome. New drugs like ADH-503 offer hope by directly targeting the cellular problems caused by MECP2 mutations, potentially leading to more effective and long-lasting treatments.

The study’s focus on microglial dysfunction and the MECP2 gene suggests that ADH-503 could have therapeutic potential beyond Rett syndrome. Since microglial dysfunction is implicated in various neurological disorders, including Alzheimer’s disease, multiple sclerosis, and autism spectrum disorder (ASD), ADH-503 might be explored as a treatment option for these conditions. However, further research is necessary to determine its effectiveness in these contexts, possibly by using transgenic mice models. The clinical trials need to be diverse, considering all kinds of populations Rett’s disease may affect.

Overall, while the findings are highly promising, particularly for Rett syndrome, significant steps remain before ADH-503 could become a widely available treatment: clinical trials, regulatory approval, and potential exploration into other neurological disorders. Nevertheless, focusing on the positive outcome of this research, leading scientists such as Dr. Kipnis at Washington University School of Medicine in St. Louis said the study will “move the needle, and bring the Rett community back to neuroimmunology”.