Drug Developers Researching Messenger RNA Replacement Therapies

Drug developers are showing increased interest in the use of messenger RNA (mRNA) as an alternate to gene replacement therapy.

A review in the April 2, 2013, online edition of the journal MIT Technology Review highlighted several companies planning or initiating research projects on the pharmaceutical applications of mRNA.

These molecules are attractive, as an mRNA would supply the biological instructions for producing a protein inside cells, perhaps a protein that replaces a missing or broken version inherited as part of a genetic disorder. This would be more efficient than DNA-based gene therapy (which would require the cells to make their own mRNA intermediary before producing a protein) and more effective than recombinant protein therapy. Proteins made from an injected mRNA would be less likely to induce an immune response than if the proteins were made in bacteria or yeast. Furthermore, more active drug would be available, as large scale in vitro manufacture of some proteins is not possible.

Obstacles that might hinder development of mRNA-based therapeutics include the fragility of these molecules and their tendency to generate a powerful immune response. However, companies beginning work in this field are confident they can overcome these difficulties. For example, Moderna Therapeutics (Cambridge, MA, USA) has modified mRNA by replacing nucleotides, so that the immune system no longer recognizes the molecule as dangerous. Their success so far has convinced the major pharmaceutical company AstraZeneca (London, United Kingdom) to pay USD 240 million for rights to the startup’s mRNA technology, which it hopes to use to develop treatments for cardiovascular, metabolic, and cancer patients.

Nucleotide substitutions seem to correct the problem of mRNA fragility. “Everybody considers mRNA to be the most unstable molecule you can think of,” said Dr. Christian Plank, CSO of Ethris (Martinsried, Germany), a company also developing modified mRNAs as drugs. “This opinion is still in the minds of most people and is a major reason why only a few people have thought of using it.” Fortunately, mRNA made with nucleotide analogs are more stable, and have been shown to last for up to 72 hours in the body, which is longer than for some protein therapies.

Molecules of mRNA cannot integrate into the genome and so do not present the same risk of disrupting the genome that DNA-based gene therapies do. “In general, gene therapy is a good approach, and in recent years there have been good breakthroughs, but for non-life-threatening disease, you want to avoid any potential risk you can think of, and integration into the genome is a known risk,” said Dr. Plank.

Ethris recently announced a collaborative agreement with the pharmaceutical company Shire (Dublin, Eire) to develop treatments for patients with rare diseases based on its technology.

Related Links:
Moderna Therapeutics
AstraZeneca
Ethris