Indian, Israeli and American researchers develop a drug for GNB1 encephalopathy

Researchers at the Indian Institute of Technology (IIT), Madras, 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 fewer than 100 documented cases worldwide, GNB1 encephalopathy is a type of brain disease or neurological disorder that affects people in the fetal stage.

Scientists say that delayed physical and mental development, intellectual disabilities, and frequent epileptic seizures are among the first symptoms of the disease, and since genome sequencing is an expensive exercise, not many parents choose to do it since the beginning.

According to Haritha Reddy, a former PhD fellow at IIT Madras, a single nucleotide mutation in the GNB1 gene that produces one of the G proteins, the “G1 protein”, causes this disease.

“This mutation affects the patient from the time they are a fetus. Children born with the GNB1 mutation experience delayed mental and physical development, epilepsy (abnormal brain activity), movement problems. To date, less than a hundred have been documented cases worldwide. However, the actual number of children affected is likely to be much higher, as the diagnosis is not widely available, requiring a sophisticated and expensive procedure,” Reddy told PTI from Israel, where he is conducting the investigation.

“Each cell in the human body has a wide variety of molecules and signaling pathways that help it communicate with other cells and within itself. The main signaling mechanism used by cells is ‘G protein-coupled receptor’ signaling ( GPCR),” he added. .

GPCR is a receptor that receives a signal (eg, a hormone, light, neurotransmitter) from outside the cell and transduces it into the cell.

“GPCR is present in the cell membrane and has a G protein (a?) attached to it from inside the cell. G proteins are the immediate downstream molecules that relay the signal received by the GPCR. These G proteins are present in every cell, and any malfunction will cause disease,” he explained.

Mutations in the GNB1 gene cause the neurological disorder (GNB1 encephalopathy) characterized by a general developmental delay, epileptiform activity on electroencephalogram (EEG) and seizures of various types, muscle hypotonia or hypertonia, and additional variable symptoms seen in patients .

According to Amal Kanti Bera, a professor at the Department of Biotechnology at IIT Madras, since GNB1 encephalopathy is a rare and lesser-known disease, not much research has been done on it.

“We don’t know the mechanisms underlying the disease. We don’t know how to treat this disease. So it’s important to do research on GNB1 encephalopathy. We have a long way to go. It’s not easy to develop.” a drug to treat this disease effectively,” he told PTI.

“We are in the process of developing preclinical animal models of this disease. Hopefully, in three years we will be able to develop personalized models of the disease that will be useful in research and drug screening,” he told PTI.

Nathan Dascal, a professor at Tel Aviv University, explained that since developmental problems start at the fetal stage, gene therapy is the most plausible option to alleviate the effects of the mutation. However, the development of this complicated procedure will take many years and a large investment of funds.

“On the other hand, epilepsy can be treated with specific medications to increase the patient’s quality of life. To treat epilepsy, specific targets must be identified. Most epilepsies are due to impaired function of ion channels. Ion channels are proteins that underlie the electrical activity of neurons and heart cells.

“It is also possible that a combination of already existing drugs will help in a personalized treatment line for the rare disease. As in the case of Covid, no new drug was found, but already available drugs became part of the treatment protocol “, said.

The research was supported by an Indo-Israeli binational grant offered by the Israel Science Foundation (ISF) and the Indian University Grants Commission (UGC).

Professor Dascal noted that whole genome sequencing, the elucidation of the complete genetic analysis of the baby, can be very helpful in early diagnosis of the disease.

“We found that the function of a potassium channel called the G-protein-controlled internal rectifying K+ channel (GIRK) (present in the brain, heart, and endocrine glands) is significantly affected. We then used drugs specific to correct channel activity.

“Since the I80T mutation is the most prevalent variant in patients with GNB1 encephalopathy, we are currently focusing on prioritizing only this mutation. We have mouse models with I80T, K78R, and D76G mutations. We have generated induced pluripotent stem cells (iPSCs) at from the patient fibroblasts with I80T mutation.

“We will differentiate patient-derived iPSCs into neurons. Our study paves the way for testing in animal models or patient-derived neurons to develop concrete therapeutic approaches,” he said.

(Only the headline and image in this report may have been modified by Business Standard staff; all other content is auto-generated from a syndicated feed.)

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