Science Sub-Journal: Using neurons from iPS cells can be used to test treatments for Christiansen syndrome

February 15, 2021 /--- Christian syndrome (CS) is an X-series genetic disorder characterized by reduced brain growth after birth, intellectual disability, epilepsy, and difficulties in balance and language.
new study provides new insights into the treatment of CS.
study was published in the February 10, 2021 issue of the Journal of Science Translational Medicine under the title "Human neurons from Christianson syndrome ipsCs reveal mutation-specific responses to rescue strategies."
images from Science Translational Medicine, 2021, doi:10.1126/scitranslmed.aaw0682.
"One of the main challenges in developing treatments for human brain diseases, such as CS, is to develop an experimental system to test potential therapies on human neurons," said Dr. Eric Morrow, author of the paper and an associate professor of molecular biology at Brown University in the United States.
recent years, the use of advanced stem cell therapies derived from patient tissue has provided a powerful new way to genetically transform human neurons from the patients themselves, who may receive such treatment in the future.
the new study, Morrow and his colleagues obtained blood samples from five CS patients and their unaffected brothers.
, they reprogrammed the blood cells into induced erythmic stem cells (iPS cells) and converted them into neurons in a petri dish.
result, they obtained neurons that were representative of CS patients and used them to test treatments.
Morrow said his team also used a new method of gene editing, using CRISPR-Cas9 technology to correct mutations in patients' cells back into healthy gene sequences.
CS is caused by mutations in the gene that encodes NHE6, a protein that helps regulate the acidity of the cellular structure called endosome.
past studies have shown that the loss of NHE6 causes the inner body to become too acidic, undermining the ability of developing neurons to branch and form connections within the growing brain.
loss of this important protein can be caused by a variety of genetic mutations in patients.
most CS mutations are called unsympathetic mutations, which make NHE6 impossible to produce at all;
, however, some CS patients showed misalmed mutations.
have some NHE6 mutations, but they produce less, which prevents the protein from functioning as it should.
Morrow's team tested neurons from ips cells on two main treatments: gene transfer, in which a healthy NHE6 gene is added to cells, and nutrition factors, substances that promote neuron growth, that promote connections between neurons and other neurons.
found that the response of these neurons to treatment depends on the type of mutation that exists.
gene transfer study may represent the first step in developing gene therapy and succeed in unsympathetic mutations in neurons.
the researchers inserted the functional NHE6 gene into unsympathetic mutations in CS neurons, which normally form branches.
, however, gene transfer fails completely in CS neurons with misalmed mutations.
further tests have shown that abnormal NHE6 due to the wrong mutation may interfere with normal NHE6, making gene transfer therapy ineffective in patient cells with these mutations.
In contrast, the delivery of nutrient factors, such as brain-based neurotrophic factors (BDNF) and insulin-like growth factor-1 (IGF-1), successfully promoted the normal formation of branches of all CS neurons studied, regardless of mutation type.
these preliminary results are encouraging, Morrow hopes future research will explore these treatments in animal models.
, "Our results provide a preliminary proof of concept for these treatment strategies, suggesting that they should be subject to further research," he said.
, however, we may eventually need to pay close attention to the patient's mutation category when selecting a specific treatment.
" (Bioon.com) Reference: 1. Sofia B. Lizarraga et al. Human neurons from Christianson syndrome iPSCs reveal mutation-specific responses to rescue strategies. Science Translational Medicine, 2021, doi:10.1126/scitranslmed.aaw0682.2.Neurons from blood cells enable researchers to test treatments for genetic brain disease