IIT Madras researchers, Tel Aviv University and Columbia University are studying a rare genetic brain disease called GNB1 Encephalopathy and trying to develop a drug to treat it effectively.
With less than 100 documented cases worldwide, GNB1 Encephalopathy is a kind of neurological disorder which affects individuals in the foetus stage.
Scientists say that delayed physical and mental development, intellectual disabilities and frequent epileptic seizures are among the early symptoms. Since genome-sequencing is an expensive procedure, not many parents opt for it early on.
According to Haritha Reddy, a former PhD scholar at IIT-M, a single nucleotide mutation in the GNB1 gene that makes one of the G-proteins, the ‘Gß1’ protein’ causes this disease.
This mutation affects the patient when they’re a foetus. Children born with GNB1 mutation experience mental and physical developmental delay, epilepsy (abnormal brain activity) and movement problems.
To date, less than 100 cases have been documented worldwide.
“However, the actual number of affected children is probably much greater as diagnosis is not widely available, as it requires a sophisticated and expensive procedure,” said Reddy from Israel, where she is conducting the research. “Every cell in the human body has a wide variety of signalling molecules and pathways that help in communicating with other cells and within itself. The major signalling mechanism used by cells is G-Protein Coupled Receptor (GPCR) signalling.”
The GPCR is a receptor that receives a signal – a hormone, light, neurotransmitter – from the outside of the cell and transduces it to the inside of the cell. “GPCR is present in the cell membrane and has a G-protein attached to it from inside the cell. G-proteins are the immediate downstream molecules that relay the signal received by the GPCR. These proteins are present in every cell, and any malfunction will cause disease,” she explained.
Mutations in GNB1 gene cause GNB1 Encephalopathy are characterised by general developmental delay, epileptiform activity in the electroencephalogram (EEG) and seizures of several types, muscle hypotonia or hypertonia, and additional variable symptoms.
According to Prof Amal Kanti Bera, biotechnology department, IIT-M, due to the rarity of the disease, not much research has been done on this. “We don’t know the mechanisms that underlie the disease or even how to treat it. Therefore, it’s important to continue researching on it,” he said. “We’re in the process of developing preclinical animal models of this disease. Hopefully, in 3 years, we’d be able to develop personalised disease models that’d be useful in research and drug screening.”
The strong neurological impact of GNB1 mutations indicates that Gß1 is involved in specific aspects of neuronal signalling. A recent proteomic study identified strong link between human epilepsies and Gß1 protein levels in different brain regions.
Prof Nathan Dascal at Tel Aviv University explained that gene therapy is the most plausible option to alleviate the effects of mutation. However, the development of this complicated procedure will take many years and great investment of funds.
“On the other hand, epilepsy can be treated using specific drugs to increase the patient’s quality of life. Most epilepsies are caused due to altered ion channel function. Ion channels are proteins that underlie the electrical activity of neurons and heart cells. It’s also possible that a combination of already existing drugs helps in treating this disease. Like in case of COVID, no new drug was found but already available drugs became part of treatment protocol,” he explained.
The research was ably supported by the Indo-Israel Binational grant offered by the Israel Science Foundation (ISF) and the India’s University Grants Commission (UGC).
Professor Dascal pointed out that whole genome sequencing (elucidation of the full genetic analysis of the baby) can be very helpful in early diagnosis of the disease. “We’ve found that a potassium channel called G-protein gated Inwardly Rectifying K+ (GIRK) channel (present in brain, heart and endocrine glands) function is affected significantly. Then we used specific drugs to correct the channel activity. As I80T mutation is the most prevalent variant in GNB1 encephalopathy patients, we’re focusing on prioritising this mutation alone. We’ve mouse models with I80T, K78R and D76G mutations. Our study paves the way for testing in animal models or patient-derived neurons to develop concrete therapeutic approaches,” he said.
Original News Link
https://www.dtnext.in/tamilnadu/2022/12/28/researchers-from-in-israel-usto-develop-drug-to-treat-rare-disease
