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#apaperaday: RNA-based drugs and regulation: Toward a necessary evolution of the definitions issued from the European Union legislation

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: RNA-based drugs and regulation: Toward a necessary evolution of the definitions issued from the European Union legislation

Today’s pick is from Frontiers In Medicine by Guerriaud et al on the definitions of RNA therapies in EU regulatory legislation. DOI 10.3389/fmed.2022.1012497. Everyone knows about mRNA vaccines by now and most followers may even have received an mRNA vaccine for COVID-19. There are also other RNA therapies that are approved (e.g. antisense oligonucleotides ASOs, siRNAs, aptamers).

The problem the authors discuss is that these RNA therapies do not really ‘fit’ in the different regulatory boxes for drugs. ATMPs (advanced therapeutic medicinal products, which contain gene TMPs and cell TMPs) and chemical drugs. ATMPs should be produced by a biological source.

The problem is that RNA therapies are often produced by an oligonucleotide synthesizer (not a biological source). Antisense oligonucleotides (ASOs) and siRNAs often have chemical modifications, but mRNA can be very similar if not identical to regular mRNAs.

Authors outline that for mRNA therapies there are different classes. Vaccines for infectious diseases (such as the COVID-19 vaccines) that aim to prevent disease. These are classified as vaccines for infectious diseases. However, cancer vaccines are GTMPs. Authors outline that there does not seem to be a clear reason for this distinction and that it likely emerged historically. However, they do outline that the GTMP cancer vaccine aims to cure/treat, while the vaccines for infections aim to prevent.

As such, the population exposed to the vaccines for infections are much larger and also include children. For cancer vaccines and CAR-T cells, there are two flavors: CTMP when the mRNA is gone by the time cells are injected into the patient and GTMP when mRNA is still present.

While for ASOs and siRNA things are less ‘grey’ because they are chemically modified, authors discuss that some will perhaps become more ‘grey’ in the future when new chemical modifications arise. Genome editing would be its own class as DNA is modified, even with synthetic guide RNAs. This is because the cas9 targets DNA. Note that for some applications cas9 and guideRNAs delivery is with a viral vector. Then obviously this is a GTMP.

Now why would it be a problem whether RNA therapies are GTMPs or chemical drugs? This is because different drug categories have different quality and safety criteria. For ASOs/siRNA neither category is really fit for purpose.

Making ASOs also GTMPs would reduce redundant safety studies, but would also mean excluding germline transmission and collecting safety data for 30 years, which is not that relevant for ASOs as it has never been shown that they can integrate into the DNA.

Authors stress that specific guidelines for RNA therapeutics and ASOs are warranted to ensure that relevant safety studies are done (not redundant but adding relevant studies not done for chemical drugs).

I agree with the authors that the lack of a proper ‘bin’ to quality ASOs is challenging – this problem has been around for a while and legislation hopefully will ‘catch up’. The challenge is that scientific breakthroughs go quicker than legislation changes. This makes sense & it is good to see that this issue now appears to be on the agenda of regulators and law/policy makers.