A-New-Era-of-Genome-Editing.

The world of science is full of DNA modifications as a therapy to cure diseases and you have already heard enough of it.

. For now, let’s skip them and come towards RNA editing as a treatment for rare genetic disorders. Previously, scientists had come up with the idea of rare genetic disorders being diagnosed and treated by RNA implications. Moving one step ahead researchers developed a programmable RNA editing technique “RNA targeting capabilities” as a therapy for rare diseases such as Duchenne Muscular dystrophy. This disease leads to abnormal protein production and progresses towards a huge loss of muscles resulting in a group of symptoms like trouble walking, curved spine, heart, and swelling problems. It is possible to correct the messages of abnormal genes by using RNA editing. “It really opens a world we haven’t seen before,” Stafforst says. . (An international leader in RNA editing research)

The illness is inherited that’s found in patients around the world and is predominant in France, northern Africa, and parts of South America. Although children with the malady can live regularly at young ages, over time their breaking down muscles prevents them from joining in several childhood activities.

Types of RNA editing:

Four basic bricks of RNA Adenosine (A), Guanosine (G), Uridine (U), and Cytidine (C) are modified in the RNA editing process by introducing insertions and deletions in these nucleosides. Two common approaches to this technique are observed in people: Adenosine to Inosine (A-to-I) modification involved the use of adenosine deaminase acting on RNA (ADARs) and Cytidine to Uridine (C-to-U) modification involved APOBEC1 (apolipoprotein B enzyme catalytic subunit 1).  With the help of Deaminase proteins, hydrolytic cleavage happens with the requirement of water molecules. Scientists are confused about this idea and why it emerges? There are two major reasons for the emergence of RNA editing. First, to correct DNA errors in the genome through RNA. Second, it introduces protein diversity in the genome, the same gene produces different proteins that can be targeted and modified. Corrections made in RNA by using deaminases proteins are shown in figure.

      

Preference over DNA editing:

The question that arises here is why we need RNA editing when there’s still DNA editing? RNA might play a regulatory role but this editing act on selective tissues, not every person produces enough amount of protein that is required for the editing process. Off-target effects also create problems. These are unwanted mutations in other sections of the genome caused by editing. RNA gives temporary off-target effects as it is degraded by the cell after performing its role so error never remains permanent. However, DNA editing produced permanent off-target effects. If we talk about CRISPR-based DNA editing in which Cas9 isolated from bacteria creates potentially hazardous immunological reactions in humans. ADARs are human proteins that don’t elicit an attack from the immune system. RNA editing will be useful for disorders that aren’t caused by a genetic mutation. For example, there are certain pain receptors in the brain. By using DNA editing, permanent changes are incorporated into the genome and it could abolish the ability to experience pain. By using RNA editing in certain tissues we can relieve pain temporarily without the risk of addiction that comes with traditional medications. Although RNA editing is beneficial there are still several obstacles to overcome before the technology can be tested in humans. To begin with, RNA is a relatively unstable molecule that requires special handling. Researchers are attempting to develop a delivery mechanism that will allow the guide RNA to be directed to its intended site while also safeguarding it from destruction. RNA editing is limited to two types of modifications either Adenosine to Inosine or Cytosine to Uracil. As deaminase proteins are not efficient so, more enzymes need to be engineered.

References

Christofi, T.; Zaravinos, A. RNA Editing in the Forefront of Epitranscriptomics and Human Health. J. Transl. Med. 2019, 17 (1), 319. https://doi.org/10.1186/s12967-019-2071-4.

(Conticello, S. G. The AID/APOBEC Family of Nucleic Acid Mutators. Genome Biol. 2008, 9 (6), 229. https://doi.org/10.1186/gb-2008-9-6-229.

Stafforst, T. & Schneider, M. F. Angew. Chem. Int. Ed. Engl. 51, 11166–11169 (2012).

Bass, B. L. & Weintraub, H. Cell 55, 1089–1098 (1988).

Montiel-Gonzalez, M. F., Vallecillo-Viejo, I., Yudowski, G. A. & Rosenthal, J. J. C. Proc. Natl Acad. Sci. USA 110,

Woolf, T. M., Chase, J. M. & Stinchcomb, D. T. Proc. Natl Acad. Sci. USA 92, 8298–8302 (1995).

Matthews, M. M. et al. Nature Struct. Mol. Biol. 23, 426–433 (2016).

Katrekar, D. et al. Nature Methods 16, 239–242 (2019).

Abudayyeh, O. O. et al. Science 365, 382–386 (2019)