A new study by an Indian-origin researcher has questioned some of the mechanisms underlying a new class of drugs based on gene silencing.
Dr. Jayakrishna Ambati, a University of Kentucky researcher has been investigating gene silencing since a long time and his study indicates that the mechanisms behind it are different from what is believed.
Also, this new work offers a need for caution in current clinical trials using the the process, as it may have potentially harmful effects on subjects.
In 1998, researchers discovered a class of double-stranded RNA (dsRNA) having powerful gene-silencing capabilities, or the ability to "turn off" disease-causing genes in the body. Later, synthetic molecules called small-interfering RNA (siRNA) were used to target these dsRNA for single genes with the belief that siRNA could interfere with specific disease-causing genes and prevent them from being expressed.
This approach became popular, as gene-targeted silencing with siRNA does not involve permanent DNA mutations. And now, this breakthrough, with the powerful ability to turn off genes, has become a standard research tool for genetic studies, and has resulted in a new class of drugs for silencing disease-causing genes in the body or deactivating an invading virus by removing its genes.
There was a surge of on-going clinical trials as many diseases like age-related macular degeneration, diabetes, kidney disease, cancer, Lou Gehrig's and Parkinson's have been heralded as candidates for siRNA therapy.
The researchers also made an important discovery challenging the observation that siRNA's therapeutic effects are only accounted to RNA interference, and argued that siRNA functions generically and not specifically. Therefore, the new class of drugs being formulated may negatively affect blood vessel growth in many organs.
"siRNAs are used in every area of biomedical research and are thought to be exquisitely specific in targeting a single gene. My lab made the surprising discovery that siRNAs, including those in clinical trials, do not enter cells or trigger RNAi. Rather, we found that they generically, regardless of their sequence or target, bind a receptor known as TLR3 on cell surfaces and block blood vessel growth in the eye, skin and a variety of other organs," Nature quoted Ambati, as saying.
It was found that if blood vessel growth is blocked, it would prove to be useful in a number of diseases. But, if blood vessel growth is blocked by intravenous administration of siRNA , it could be harmful if it impacts other organs. But Ambati maintains that the Nobel Prize-winning discovery is still valid.
"RNA interference does, of course, exist. It is just that siRNA functions differently than commonly believed - not via RNA interference," said Ambati.
According to him, his research has two-fold implications, not only for researchers in understanding the working of siRNAs but also for clinical trials of siRNA to be approached with great caution.
Besides, it was also shown that people with a mutation in the TLR3 receptor would not be susceptible to the generic effects of siRNAs, and thus raising hope for personalized medicine in this population.
The study is published in the recent issue of Nature.