How “Turning down” the volume of the faulty gene can cure a disease
Heart disease has a certain long and profound history in human medical history, Scientists majoring in these specific genera’s have spent their life researching these said cardiovascular diseases and finding a solution to all the related heart diseases using modern techniques. Twelve years ago one said scientist named Euan Ashley spent his hours developing his idea to revolutionalize cardiovascular medicine. Part cardiologist and part geneticist Ashley, D.Phil, FRCP was developing specific ways to repair heart cells damaged over time due to numerous reasons, In the case which he was studying, the condition he was looking into is called as “cardiomyopathy”. This disease specifically affects the pumping ability of the human heart that results in a weakened heart state and causes a decreased circulation of blood in the body. The main types of it include dilated hypertrophic and restrictive cardiomyopathy. Ashley at that time was thinking of a way to counteract this disease by using certain steps and processes that involves RNA silencing. This process basically aims at deactivating the genes that are involved in unusual cardiac rhythms, thus restoring the genomic makeup that causes the heart to function normally again.
But the major problem was that Ashley didn’t quite have any idea about RNA silencing but fortunately he knew someone who did know about it alot, Andrew Fire, a Ph.D. professor of genetics and pathology, and a recent Noble prize winner at that time who won the prize for discovering the same biological mechanism that Ashley wanted to study. Despite not having any knowledge about the technique he wanted to work on, Ashley wasn't ready to back up because of that and wanted to develop an understanding regarding RNA silencing, so he sent Andrew Fire a message requiring his assistance on the matter. Talking about that call for help, Ashley said,
“So I sent him a message out of the blue, saying ‘Dear Professor Fire, you don’t know me, but I’m a new assistant professor here at Stanford and I wonder if there’s any chance I could pick your brain about an idea I have.”
And then something happened which Ashley was not really expecting. Not five minutes later, his phone rang.
“At that time I was so new, 90% of my calls were wrong numbers. So, when I answered, and the other person said, ‘Hi it’s Andy,’ I racked my brain — I didn’t know any Andys.”
The phone call led to a long discussion between the two. and when it concluded, Ashley was finally ready to start his long waited research project which aimed to develop a new gene therapy treatment for cardiomyopathy. Because of the knowledge, he got from the Nobelist Andrew fire and a hard work of over a decade, he finally got the breakthrough he wanted.
Ashley’s first breakthrough was the solution for certain cardiomyopathy types, and especially emphasizing on “Restrictive cardiomyopathy”, a type that causes a type a stiffness in the heart’s blood vessels ultimately reducing the blood flow to the other parts of the body and the organs that need blood the most are seriously affected by this condition. He tested the idea in mice using targeted gene therapy using RNA silencing.
From their on, he continued his research on cardiomyopathy and after 12 long years of effort Ashley published his first paper In “Circulation” regarding the same technique for cardiomyopathy detailing the successful approach he came up with for treating the disease. The Targeted gene therapy already proved to be a safe procedure when it was tested on mice was labeled clear for further laboratory processes deeming the full efficacy of the process and making it viable for further clinical trials. Ashley research work, as well as the paper, is also attributed to Mathew Wheeler, MD, assistant professor of medicine and Kathia Zaleta-Rivera.
So how does the process works basically? well, Ashley focused on certain genes that were involved in the restrictive cardiomyopathy. His research included special types of genes that are involved with the abnormality of the heart cells. These two genes when considered the cause of Restrictive cardiomyopathy, for simplicity described as MYL2. Since the first testing was on mice, Ashley did not have to deal with many complications as the genetic makeup is almost similar to humans that means they have the copy of the same gene. In mice, however, the study showed that out of the two genes present in a MYL2 sick mouse, one was mutated and the other copy surprising was functioning normally.
This indicated Ashley that at least one of the MYL2 gene copies in a sickened person must be producing a normal protein and he thought at that moment as he described it,
“We wondered if we could essentially ‘turn down’ the volume of the signal sent by the mutant gene copy.” Then, with the faulty copy turned down, the healthy copy could carry out the gene’s proper function.”
Ashley carried out his Idea of RNA silencing using different processes and methods over the year. His team of scientists also used special viruses for the cause that were genetically altered by removing their standard viral contents and infusing them with the specific testing material that modifies the abnormal heart cells in order to turn it down. The alternated virus also contained a guiding gene that directs the virus to act on the specific mutated copy that is present.
Recently successful clinical trials in mice proved that the modified virus used in this experiment had the necessary materials that can significantly lower the chances of restrictive cardiomyopathy in mice, therefore there is a good chance that it might as well do it in humans too hopefully. the recent results also showed that without treatment the life span in mice was of 30–50 days, but the treatment increased the life span. Talking about the results Ashley said,
“We measure something called fibrosis, which is about as close as we can get to measuring heart stiffness, and in those mice that were treated, we sw about a 25% drop in fibrosis”.
Keeping Ashley’s mice test in mind there is a good chance that this therapy will work positively on humans. After their success on mice, Ashley and his team of scientists are running the test on human blood cells of patients affected by Cardiomyopathy. Human trials will start soon after, and it is believed that with this effective targeted gene therapy technique the people with the disease can be completely treated in the near future.
Refrence
https://scopeblog.stanford.edu/2019/08/20/turning-down-the-volume-of-a-faulty-gene-in-heart-disease/
