RNA-based therapies: beyond vaccines

The recent approval of different vaccines against SARS-CoV-2 has shown the usefulness of RNA in different medical applications. This technique allows the body to produce a protein that is not encoded in human genes, which is a huge advance in the field of medicine. But in addition to allowing the development of new vaccines, there are other clinical uses for RNA. In this article we will explain what they are.

RNA functioning

RNA based therapies
RNA based therapies

Ribonucleic acid or RNA is a molecule made up of subunits called nitrogenous bases. It is similar to DNA, but it has different functions. While DNA stores the genetic information of an organism, encoding the expression of different proteins, RNA acts as a link between DNA and ribosomes, cellular organelles responsible for synthesizing proteins. This is the case of messenger RNA or mRNA, but there are also specific types of RNA that perform regulatory functions of gene expression, such as interfering RNA or RNAi, which inhibits the expression of certain genes.

Whereas traditional vaccines introduce a weakened pathogen, or the proteins characteristic of the membrane of said pathogen, into the body, mRNA-based vaccines consist of an mRNA sequence that encodes the protein of interest, so that the cells can produce it and the immune system identifies it and is able to respond in the future if it comes into contact with the pathogen.

But back to the big picture, this technology can be used for other applications besides training the immune system to recognize new pathogens. It not only allows the synthesis of viral or bacterial proteins, but any type of protein. This includes human proteins that a person cannot produce due to some genetic defect. For example, certain types of muscular dystrophies are due to errors in muscle protein synthesis. 

Treatment of muscular dystrophy with CRISPR and RNA

The most common type of muscular dystrophy is type 1 myotonic dystrophy . It is due to an excessive number of repetitions of an amino acid sequence in a gene that codes for a muscle protein (DMPK gene). This causes the resulting mRNA to be excessively long and cannot be used to synthesize muscle protein, causing progressive muscle degeneration.

One tool used in innovative gene therapies is CRISPR , which consists of the use of DNA sequences to detect and destroy other specific DNA sequences. This can be used to inactivate or alter the functioning of certain genes. One of the enzymes associated with the CRISPR system is Cas9, which acts on a specific DNA sequence using a guide RNA sequence.

In a recent study carried out with mice, the Cas9 enzyme was used to act directly on mRNA sequences that contained an excess of repetitive sequences , eliminating these sequences and resulting in a functional mRNA fragment capable of synthesizing the muscle protein that could be used. otherwise it could not be expressed.

Regulation of protein synthesis

Another disease related to inadequate protein synthesis is amylodiosis . This disease consists of the accumulation of abnormal proteins, called amyloids , in certain organs, causing errors in their functioning. These proteins are difficult to remove, because they are insoluble and resistant to the usual protein degradation carried out within cells. It is a degenerative and fatal disease.

A drug for the treatment of this disease has recently been approved for sale, consisting of RNAi that silences the expression of the defective transthyretin protein, one of the causes of amylodiosis. This is the first RNAi treatment available, and it is the first effective treatment for amylodiosis.

Spinal muscular atrophy treatment

Spinal muscular atrophy is a group of pathologies with a genetic basis associated with the incorrect expression of the SMN1 gene, which implies the deficiency of certain motor proteins. It is an important cause of infant mortality, as it entails a series of motor and respiratory problems that shorten the life expectancy of those who suffer from the disease.

The cause of this disease is an incorrect maturation of the mRNA once it is synthesized, which results in non-functional defective copies that are not capable of expressing the protein. This has been corrected by a drug that blocks the wrong step in the maturation of this mRNA, thus increasing the amount of protein available.

This drug is supplied directly into the cerebrospinal fluid of the lumbar region, requiring only about four applications throughout the year, thanks to the long duration of its effect. If it is applied before the symptoms of the disease appear, it can be prevented, or its expansion can be stopped if it has already begun.

As explained in the previous examples, RNA therapies include different techniques that allow to modulate gene expression in a precise way, to avoid the effects of diseases that would otherwise be fatal. They are especially interesting techniques for the treatment of rare diseases, which have a low incidence in the population but whose effects are usually fatal.

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