Stem Cell Model Developed for Rare Neurological Condition

Researchers at the UC – San Diego School of Medicine have led an international team of investigators to create a stem cell model for a rare neurological condition known as Aicardi-Goutieres Syndrome (AGS).

AGS: A Devastating Neurological Condition

Aicardi-Goutieres Syndrome (AGS) is an inherited autoimmune disorder that is progressive and associated with inflammation in the brain, skin, and immune system. Six types of genes are involved and can cause AGS of varying severity. The devastating consequences of the condition include a small head (microcephaly), psychological and physiological effects, vision problems, skin spasticity, and joint stiffness.

The disorder manifests early, typically in the first year of life. By early childhood, the afflicted individual ends up in a vegetative state. Treatment is limited to symptom control and palliation.

Pathogenesis of AGS

The disorder mimics acquired in utero viral infections, but scientists have been unable to identify any link between AGS and a specific exogenous pathogen. Research has shown that patients with AGS have a mutation in the genes that regulate the immune response of cells and nucleic acid metabolism. A deficiency of the enzyme called TREX1 has been noted in these patients. TREX1 is responsible for preventing the accumulation of abnormal DNA in cells.

Genetic Research into Aicardi-Goutieres Syndrome

The international team of researchers first identified the genetic mechanisms that cause AGS. These findings allowed them to test drugs and strategies to inhibit the disorder. In particular, two FDA-approved medications were successful in rescuing cells from the inflammatory response of AGS. The results published in Cell Stem Cell are encouraging that novel stem cell models can be used to study human disorders for which no treatments or disease models are currently available. Neurological conditions such as schizophrenia and autism as well as other autoimmune disorders can be investigated with similar stem cell models, explains Alysson Muotri, director of the Stem Cell Program at UC – San Diego.

Stem Cell Model for AGS

AGS has been challenging to study because animal models do not mirror the progress of the disorder in humans. Muotri and colleagues obtained induced pluripotent stem cells and embryonic stem cells from patients afflicted with AGS and developed six stem cell models. This disease-in-a-dish approach has been previously used for diseases such as Williams Syndrome, anorexia nervosa, autism, and other rare neurological disorders.

The team used iPSCs to create organoids or mini-organs which are essentially clusters of neurons organized into a structure resembling the cerebral cortex in humans. With dysfunctional TREX1 enzyme, the cells models accumulated excess junk DNA (repetitive sequences of jumping genes that have no known function). The team had previously identified L1 retroelements in repetitive sequences as having a big impact on brain cells and creating genetic mosaicism.

The researchers looked outside the nucleus of the cell and found that in the stem cell models of AGS, toxin build up and abnormal immune responses were leading to cell death and reduced neuron growth. A similar picture is seen during fetal development during progression of AGS. This novel mechanism where L1 molecules outside the nucleus impact neuronal development is not evident in animal (mice) models and is unique to humans.

AGS and HIV Drugs

Since the pathogenesis of AGS was found to be similar to infection with retroviruses such as HIV, the team tested two drugs – Lamivudine and Stavudine – to see if they would interfere with the replication of L1 molecules. Both drugs reduced cellular toxicity and L1 activity and led to improved growth of the organoids in the stem cell models. This would suggest that HIV drugs may be beneficial for patients with AGS. Clinical trials are underway at the University of Manchester in England and Sorbonne in Paris.



Mira Swave, MD

Contributor at Regenerative Medicine Now

Mira Swave, M.D. is a specialist in the field of Regenerative Medicine.
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