Experimental Cancer Drug Offers Hope for Rett Syndrome and Autism-Related Cognitive Issues

A representative culture from a brain organoid in which the gene MECP2 — causative in Rett syndrome — has been “knocked out,” as shown through a fluorescent microscope. Because the culture was treated with experimental cancer drug ADH-503, new synapses formed. Credit: Muotri Lab / UC San Diego Health Sciences

New study identifies a potential therapeutic target to improve cognitive function in patients with various neurological disorders.

New research from the University of California San Diego suggests that an experimental cancer drug may improve cognitive function in individuals with Rett syndrome, a rare condition associated with autism. This discovery holds potential for developing treatments for other neurological disorders.

The findings, published July 25 in Stem Cell Reports, highlight the role of microglia — a type of white blood cell found in the central nervous system — in the formation of the human brain.

While such cells have been better studied in neurodegenerative disorders like Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis, “very little information has existed on their role in early stages of neural development” because access to fetal tissue is limited, said Pinar Mesci, Ph.D., the study’s lead researcher. Now employed elsewhere, she completed work on the project while at the university.

In a bid to better understand their function, Mesci instead used brain organoids — “mini-brains,” essentially, that mimic the developing brain of an embryo — grown from skin-derived stem cells of consenting patients. Such organoids were created from individuals with Rett syndrome — a disorder primarily found in females that features loss of speech, purposeful use of hands, mobility, and muscle tone, among other symptoms — as well as from neurotypical individuals.

Importance of Microglia in Brain Function

Mesci then added healthy microglia to the Rett syndrome brain organoids and found that the functioning of synapses — where neurons connect and communicate — was “rescued.” This occurred due to the restoration of phagocytosis, a process by which microglia — sometimes referred to as the “janitors” of the central nervous system — ingest and destroy foreign substances like bacteria and dead cells, keeping the brain and spinal cord tidy. The process also involves “pruning” of synapses, which optimizes brain function.

Researchers also found that the synapses of typical neurons experienced impaired functioning when Rett syndrome microglia were introduced, further confirming the role of the immune cell in brain function and development.

“If the brain’s ‘janitors’ are not working, problems start to arise,” said UC San Diego School of Medicine professor Alysson Muotri, Ph.D., senior author and director of the university’s Sanford Stem Cell Institute’s Integrated Space Stem Cell Orbital Research Center.

Faulty microglia make cognition even harder for Rett syndrome patients, who already contend with fewer and impaired synapses and dysfunctional astrocytes due to a loss of function in the MECP2 gene, implicated in other types of neurodevelopmental conditions as well.

Microglia with loss of MECP2 function “are not as good at pruning synapses and shaping the neural network — they don’t do a good job,” Muotri said.

The team then tested a battery of existing drugs on the microglia, to see if any might restore phagocytosis. They found one: ADH-503, also known as GB1275 — an experimental oral pancreatic cancer medication that also reduces the number of immune-supressing cells that enter a tumor. The drug serves as a regulator of CD11b, a protein involved in phagocytosis, among other processes.

Other studies on Rett syndrome have highlighted potential therapeutic targets. But none so far have identified a potential treatment involving human microglial cells.

By the time Rett syndrome patients are diagnosed, it’s too late to repair, and not currently possible to replace faulty neurons, the primary issue in the disease. “But by focusing on other cell types — and potentially finding drugs that improve how they work — we might improve the environment for those neurons and ease functioning for patients,” Mesci said. “That’s what I’m excited about.”

Broader Implications for Neurological Disorders

Jonathan Kipnis, Ph.D., professor of pathology, immunology, neurology, neuroscience, and neurosurgery at Washington University School of Medicine in St. Louis and director of its Brain Immunology and Glia Center, said the new research “nicely demonstrates” microglia as a potential therapeutic target in Rett syndrome.

“I hope this work will ‘move the needle’ and bring the Rett community back to neuroimmunology,” Kipnis said. “Understanding neuro-immune interactions in this complex disease may not only provide new insights into the disease biology, but also develop novel approaches to attenuate its progression.”

The research represents the first successful integration of human microglia into Rett syndrome brain tissues in vitro — a model that may prove superior to mouse models.

The researchers hope the study “opens doors for therapies,” not only for those with Rett syndrome, but for those with other neurodevelopmental and neurodegenerative disorders in which microglia play a role.

“That’s my wish,” Mesci said, “that we can improve quality of life.”

Reference: “Human microglial cells as a therapeutic target in a neurodevelopmental disease model” by Pinar Mesci, Christopher N. LaRock, Jacob J. Jeziorski, Hideyuki Nakashima, Natalia Chermont, Adriano Ferrasa, Roberto H. Herai, Tomoka Ozaki, Aurian Saleh, Cedric E. Snethlage, Sandra Sanchez, Gabriela Goldberg, Cleber A. Trujillo, Kinichi Nakashima, Victor Nizet and Alysson R. Muotri, 25 July 2024, Stem Cell Reports.
DOI: 10.1016/j.stemcr.2024.06.013

Co-authors of the study include Christopher LaRock, with the Department of Pediatrics at the University California San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences; Jacob J. Jeziroski, Natalia Chermount, Tomoka Ozaki, Aurian Saleh, Cedric E. Snethlage, Sandra Sanchez, Gabriela Goldberg, Clever A. Trujillo and Kinichi Nakashima, with the University of California San Diego School of Medicine and Department of Pediatrics at Rady Children’s Hospital San Diego, and the Department of Cellular & Molecular Medicine; Hideyuki Nakashima, with the Department of Stem Cell Biology and Medicine at Kyushu University’s Graduate School of Medicine; Adriano Ferrasa, with the Experimental Multiuser Labratory at the Graduate Program in Health Sciences at the School of Medicine at Pontifícia Universidade Católica do Paraná in Curitiba, Paraná, Brazil, as well as the Department of Informatics at the Universidade Estadual de Ponta Grossa in Ponta Grossa, Parana, Brazil; Roberto H. Herai, with the Experimental Multiuser Labratory at the Graduate Program in Health Sciences at the School of Medicine at Pontifícia Universidade Católica do Paraná in Curitiba, Paraná, Brazil, and the Research Department at Lico Kaesemodel Institute in Curitiba, Paraná, Brazil; and Victor Nizet, with the Department of Pediatrics at the University California San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences.

This work was made possible in part by the California Institute for Regenerative Medicine (CIRM) Major Facilities grant (FA1-00607) to the Sanford Consortium for Regenerative Medicine. Muotri is supported by the National Institutes of Health (NIH) R01MH107367, R01HD107788, R01NS105969 and R01NS123642, and a grant from the International Rett Syndrome Foundation (IRSF). This work was also partially funded by the IRSF Innovation Award granted to Mesci (grant No. 3905). Herai is funded by Fundação Araucária (grant No. FA09/2016). This work was also partially funded by AMED (JP22mg1310008), an Intramural Research Grant (3-9) for Neurological and Psychiatric Disorders of NCNP grant to Nakashima and a Japan Society for the Promotion of Science (JSPS) KAKENHI (JP22K15201) to Nakashima. This publication includes data generated at the UC San Diego IGM Genomics Center utilizing an Illumina NovaSeq 6000 that was purchased with funding from an NIH SIG grant (No. S10 OD026929).

Disclosures: Muotri is a co-founder and has an equity interest in TISMOO, a company dedicated to genetic analysis and human brain organogenesis focusing on therapeutic applications customized for autism spectrum disorder and other neurological disorders with genetic origins. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict-of-interest policies. The authors have a patent application in the works related to this publication.