Contact:
sales@biotechnologyforums.com to feature here

Thread Rating:
  • 0 Vote(s) - 0 Average
  • 1
  • 2
  • 3
  • 4
  • 5
Using viral vectors to mediate miRNA therapeutics
#1
miRNA’s can be utilized for a number of purposes, and recent research in this field has been prolific and detailed. Along with miRNA’s great potential as biomarkers for different pathological states and as useful diagnostic tools, miRNA’s can also be used as potent therapeutics. Benjamin tenOever, Ph.D., professor of medicine at Mount Sinai School of Medicine, has been working on figuring out how miRNAs can be utilized in engineered RNA-based vectors for therapeutic purposes.

The majority of the discovered and known miRNA genes is intergenic or oriented antisense to adjacent genes and is therefore thought to be transcribed as independent units. However, it has been discovered that in some cases a microRNA gene is transcribed together with its host gene which provides a means for coupled regulation of miRNA and a protein-coding gene. The main function of miRNAs appears so far to be gene regulation. For this purpose, a miRNA is usually complementary to a part of one or more messenger RNAs.

Dr. tenOever’s lab has successfully developed a new method for exploiting endogenous miRNAs to regulate tissue tropism of viral vectors.

“Because viruses lack a mechanism for antagonizing miRNA function, we can exploit miRNA expression to control viruses. We have shown that if you incorporate targets for a cell-specific miRNA into an RNA virus genome, you can create a virus that looks identical at a protein level but would be selectively blocked from infecting these particular cells.” – says Dr. tenOever

On the other side, Dr. tenOever’s research has focused on engineering viral vectors that can produce functional miRNAs, which can be used as a therapeutic platform, of the vector type, to deliver miRNAs or any other small RNAs to practically any tissue in the body. Dr. tenOever states that, while it has already been known that RNA viruses do not produce miRNAs, it was not clear whether viruses simply lack the capacity to do so, or whether this specific activity was perhaps detrimental, or in some other way harmful, to the viral life cycle.
The researchers decided to approach this question by incorporating primary miRNAs (pri-miRNA) into various available RNA viral vectors that are known to localize to the nucleus or the cytoplasm in different tissues. In all their tests, mature miRNAs were properly processed and loaded into the RISC complex. In the case of cytoplasmic viruses, an RNase named Drosha was exported out of the nucleus into the cytoplasm to process the artificial pri-miRNA.
After the experiments the team concluded that it appears most RNA viruses are in fact capable of producing functional miRNAs, but avoid to do so in natural cases, which is not yet clear as to why, presumably to prevent some degree of self-attenuation.

“What we can capitalize on now is to convert an miRNA that behaves like a tailor-made, sequence-specific siRNA. We can then adapt any RNA virus, regardless of tropism, and use it to generate siRNAs to silence a desired host gene,” Dr. tenOever reported.

The artificial RNA viruses only produce miRNAs for 7–10 days afer being implanted, but nonetheless, they have show a great capacity for usefulness, and many transient cytoplasmic RNA viruses have become very useful in Dr. tenOever’s lab for a great variety of applications, some of them as reprogramming of fibroblast cells into iPSCs by introducing a few miRNAs.
“The advantage of our system is that we are not going into the nucleus with our vectors and we’re not integrating into the genome; we’re only there for 7–10 days and then our vectors disappear, but by then we have reprogrammed our cells to become pluripotent stem cells.”

This new approach using the recently discovered miRNA’s has great potential, in research as well as medicine and the clinical approach. By using miRNA in combination with recombinant RNA viruses as transition vectors, future research might offer a way of ‘reprogramming’ the body’s cells for a variety of purposes, ranging from therapeutics, diagnosis and prevention of various diseases and pathological states.


Resources:
Tuddenham L, Jung JS, Chane-Woon-Ming B, Dölken L, Pfeffer S (February 2012)."Small RNA deep sequencing identifies microRNAs and other small noncoding RNAs from human herpesvirus“
Place RF, Li LC, Pookot D, Noonan EJ, Dahiya R (2008). "MicroRNA-373 induces expression of genes with complementary promoter sequences"
Krol J, Sobczak K, Wilczynska U, Drath M, Jasinska A, Kaczynska D, Krzyzosiak WJ (2004). "Structural features of microRNA (miRNA) precursors and their relevance to miRNA biogenesis and small interfering RNA/short hairpin RNA design".
Like Post Reply
  

Possibly Related Threads…
Thread
Author
  /  
Last Post
Replies: 0
Views: 8,197
04-19-2013, 01:24 AM
Last PostNikolas



Users browsing this thread:
1 Guest(s)

Using viral vectors to mediate miRNA therapeutics00