In addition to vaccines, can mRNA be used to treat diseases?

The remarkable success of the two Covid 19 vaccines in clinical trials is a major breakthrough for medical technology that has not been proven before. Last week, one of the vaccines received an emergency use permit from the US Food and Drug Administration. These vaccines rely on genetic instructions known as messenger RNA (mRNA). These instructions cause the cells to make one of the SARS-CoV-2 proteins, which trains the immune system to detect the virus.

Long before the birth of Covid 19, mRNA was considered a simple and flexible way to deliver vaccines and drugs. A specific sequence of mRNA may repair a damaged heart by producing a protein that stimulates the growth of blood vessels. Also, another sequence may encode an enzyme that can reverse a rare genetic disease.

Protein synthesis

RNA messenger (blue) directs cell ribosomes to make new (red) proteins

گوراو سهایThe success of Covid vaccines has created a storm of enthusiasm for the concept, says Oregon State University pharmacist. However, mRNA drugs, especially those that replace defective proteins that are useful for chronic diseases, have a harder way to get to clinics than vaccines. These drugs face the challenge of targeting mRNA for specific tissues and delivering strong, lasting benefits without excessive side effects.

Few of these treatments have been included in clinical trials. Helen Dwight“It’s not like inserting another sequence into the body and treating everything,” says a pharmacologist at the University of Ghent in Belgium. Matching mRNA to any disease often means manipulating the structures of the mRNA itself and the protective bubble used to deliver it to the body, called a lipid nanoparticle.

For vaccines and some mRNA drugs, it is relatively simple to use: after injection into the arm, muscle cells take up mRNA and produce viral protein, and then the immune system sees the resulting protein as an external agent and produces antibodies and T cells that the body produces. Prepares to defend against future attacks. In addition to SARS-CoV-2, mRNA vaccines against rabies, Zika, cytomegalovirus, influenza, and other viruses are being developed in clinical trials.

Also, topical injection into a muscle or under the skin or into a tumor can deliver mRNA-based therapies that use the immune system to fight cancer. Several clinical trials are underway for such therapies that encode tumor proteins or immune-transmitting molecules to help intensify the body’s attack on cancer cells.

Although several trials are testing messenger RNA to arm the immune system against viruses or cancer, only a few companies have begun small clinical trials for other therapies (such as using mRNA to replace lost or defective proteins). The table below lists some of these companies.

Companies making mRNA drug

Many other mRNA drugs must reach a specific location in the body through the bloodstream. One case is ornithine transcarbamylase (OTC) deficiency, in which a lack of an enzyme causes ammonia to accumulate in the blood, leading to seizures, coma, and death. To prevent the accumulation of ammonia, the mRNA must reach the liver cells.

Arctorus specializes in mRNA drugs and one of its goals is to treat OTC. به‌گفت‌ی Joseph PayneThe company plans to maximize the amount of drug that reaches the liver by adjusting the size and electrical charge of lipid nanoparticles. Arctorus has completed an initial safety study of about 30 healthy volunteers, and this month, 12 people with the defect received the company’s medication. One of the reasons Arctorus focused on the OTC defect was that the liver usually picks up particles from the bloodstream and collects them, which includes therapeutic nanoparticles.

James Dehlman“It’s harder to deliver mRNA to other tissues,” says a biomedical engineering expert at the Georgia Institute of Technology. Various research groups are manipulating the structure of lipid nanoparticles or embellishing them with molecules that direct them to specific organs or cells. Delhman Laboratory and co-founder Guide Therapeutics have developed a technique for tracking the path of thousands of chemically unique nanoparticles by labeling them with DNA barcodes. However, he says it will take a decade to discover the link between the structure of a lipid nanoparticle and its destination.

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The second major difference between vaccines and mRNA-based therapies is that vaccines require only one or more doses. When the immune system is trained to attack the threat, the protein produced by the mRNA is destroyed and does not need to be replaced.

According to Dehlman, mRNA drugs that have reached clinical trials so far are often drugs that have a longer-lasting effect. This is also the case for therapies that use mRNA to encode proteins such as the Cas9 enzyme. The Cas9 enzyme cleaves the genome for permanent editing.

Intellia Therapeutics, a company involved in crisper‌ genome editing, is working on mRNA-based treatment for the inherited disease amyloidosis transretirtin. The company gave its drug to the first participant in a clinical trial last month.

When repeated doses of mRNA are required to replenish protein throughout life, side effects (possibly due to accumulation of lipid nanoparticles in the body or an inflammatory response to foreign RNA) are exacerbated. That bearer“People may experience discomfort and fever for a day or two after receiving the Covid 19 vaccine,” said Translate Bio, a company active in mRNA therapies. “But to endure this situation once or more every three weeks for the rest of your life is a different proposition.”

To make repeated doses of the drug more tolerable, Translit Bio and other companies are designing mRNA that looks as natural as possible to the body and delivering it through biodegradable nanoparticles. Translite Bio mRNA treatment for cystic fibrosis is currently in clinical trials. According to the company, a single dose of this treatment did not cause any serious side effects; But some patients developed fever and muscle aches or headaches that were short-lived and manageable. Another trial is testing multiple doses.

Increasing the amount of protein the body makes from a single dose of mRNA reduces the frequency and size of doses needed. Sahai says one way is to increase the ability of lipid nanoparticles to escape those membrane sacs that the cell uses to trap them. Thus, a larger amount of nanoparticle mRNA loading has the opportunity to interact with cellular machinery to make proteins. His team reported in February that in experiments on cells, the inclusion of natural types of cholesterol in lipid nanoparticles allowed them to escape better.

Competition for the mRNA vaccine against Covid 19 has not eliminated the problem of delivery and repeated use of mRNA therapies; But it may have paved the way for them in some other way. What vaccine manufacturers have shown is that billions of nanoparticles and mRNA strands can be produced in a short time. The Saha team is still discovering the best lipid nanoparticles to accompany and deliver mRNA to remote parts of the body. He calls the achievement of such a discovery revolutionary; Because now the process of getting these treatments to the clinic is smooth.

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