Understanding the Cellular Mechanisms to Drive New Therapies for Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech and Seizures (NEDAMSS)

Understanding the Cellular Mechanisms to Drive New Therapies for Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech and Seizures (NEDAMSS) 1024 577 Jessica Nye, PhD

Derived cells from patients with NEDAMSS exhibit perturbed cellular respiration and poor neuronal survival, both of which can be improved with CuATSM treatment.

NEDAMSS (neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures) is a rare neurological disorder discovered in 2018 with only 25 formally diagnosed patients worldwide. It is primarily caused by truncation mutations in interferon regulatory factor 2 binding protein-like (IRF2BPL) and causes developmental delay, neurological regression, and seizures.

Kathrine Meyer, PhD

Kathrin Meyer, PhD

“There is no treatment for NEDAMSS. With this diagnosis you can expect your child to lose the ability to walk, to speak, to lose everything,” says Kathrin C Meyer, PhD, principal investigator in the Center for Gene Therapy at The Research Institute at Nationwide Children’s Hospital. “In my experience, there can be big discrepancies between the clinic and the science around similar diseases. Clinicians get a genetic report saying there is a truncating mutation, but that’s often not the whole story. Understanding the cellular mechanisms and what’s actually going wrong in the cells, in my opinion, is really important.”

“Our aim is to figure out the different mechanisms involved in this disease and to develop a treatment. With that in mind, four years ago I developed an in vitro model of NEDAMSS,” says Shrestha Sinha Ray, PhD, a postdoctoral fellow in Dr. Meyer’s lab.

In their in vitro model, fibroblast-derived astrocytes from four patients with NEDAMSS showed mislocalization of IRF2BPL proteins in the cytoplasm (P <.01) compared with nuclear localization in cells from healthy controls. The mislocalization of IRF2BPL proteins was also associated with fragmented mitochondrial networks compared with controls (P <.01).

To better understand the consequences of protein mislocalization on the nervous system, the investigators cultured monolayers of the derived astrocytes with mouse neurons. After three days, neurons cultured with patient cells had decreased survival compared to neurons cultured with healthy controls (P <.0001).

This pattern of neuronal survival mirrored a previous experiment that used cells from patients with amyotrophic lateral sclerosis (ALS). “One of the approaches in my lab is to look for common pathways that we can use to treat different diseases. Another postdoc in my lab, Cassandra Dennys, studied ALS patient cell lines,” says Dr. Meyer. In that study (Denneys et al., 2022), they found the copper-containing compound CuATSM (diacetylbis(N(4)-methylthiosemicarbazonato)copper(II))) was able to promote neuronal survival in ALS cells that had a mitochondrial signature that was similar to NEDAMSS cells.

Shrestha Sinha Ray, PhD

Shrestha Sinha Ray, PhD

To evaluate whether CuATSM may have an analogous effect in NEDAMSS, patient-derived astrocytes were treated with 1 mM CuATSM for four days. Treatment with CuATSM significantly improved neuronal survival in cocultured neurons (P <.05) and altered basal (P <.0001) and ATP-linked (P <.0001) respiration in cells from three of the four patients, which returned respiration levels to that of healthy controls. Importantly, the in vitro data was recapitulated in vivo by their collaborators from Baylor College of Medicine.

“Our ultimate aim is to develop a mouse model, which is a very important next step to figure out the disease phenotype in the mouse and to try and treat it with either CuATSM or develop a gene therapy for this disease. That’s no small feat, but it needs to be the next step,” concludes Dr. Ray.

 

Reference

  1. Ray SS, Dutta D, Dennys C, Powers S, Roussel F, Lisowski P, Galžar P, Zhang X, Biswas P, Caporale JR, Rajewsky N, Bickle M, Wein N, Bellen HJ, Likhite S, Marcogliese PC, Meyer KC. Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy. Cell Rep. 2022;41(10):111751.
  2. Dennys CN, Roussel F, Rodrigo R, Zhang X, Delgado AS, Hartlaub A, Saelim-Ector A, Ray W, Heintzman S, Fox A, Kolb SJ, Beckman J, Franco MC, Meyer K. CuATSM effectively ameliorates ALS patient astrocyte-mediated motor neuron toxicity in human in vitro models of amyotrophic lateral sclerosis. Glia. 2023;71(2):350-365.

Image credit: iStock

About the author

Jessica Nye, PhD, is a freelance science and medical writer based in Barcelona, Spain. She completed her BS in biology and chemistry and MS in evolutionary biology at Florida State University. Dr. Nye studied population genetics for her doctorate in biomedicine at University of Pompeu Fabra. She conducted her postdoctoral research on the inheritance of complex traits at the Autonomous University of Barcelona.