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#apaperaday: What Can RNA-Based Therapy Do for Monogenic Diseases?

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: What Can RNA-Based Therapy Do for Monogenic Diseases?

Today’s pick is a paper from Pharmaceutics by Clarke and Amaral on RNA based therapies for monogenic (rare) diseases, selected in anticipation of today’s STOA panel on the future of RNA therapeutics DOI: 10.3390/pharmaceutics15010260. Authors outline that rare diseases are individually rare, but jointly affect 6% of individuals. The title is misleading as review focuses on cystic fibrosis (CF), instead of giving a helicopter view of how different RNA therapy modalities target differently inherited diseases.

Authors focus on single stranded antisense oligonucleotides (ASOs) & mRNA therapies & CF, but also (briefly) other rare diseases. For ASOs authors focus mostly on splicing modulation. For CF this is restoration of cryptic splicing (introduction of non-coding part of gene in mRNA).

ASOs can target the cryptic exons and restore normal protein production. They can also skip regular CFTR exons that contain a mutation. When these exons are ‘in-frame’ skipping them bypasses the mutation, while still allowing the production of a partially functional CFTR protein.

In these latter cases, co-treatment with chemical drugs can improve the functionality of the internally deleted CFTRs. Note that ASO treatment for CF is still in preclinical development. Splice modulation ASOs are approved for spinal muscular atrophy and Duchenne (FDA only).

Authors discuss that for Duchenne safety of the approved ASOs is an issue. This is surprising to me as the approved ASOs are well tolerated – patients are monitored for kidney toxicity, which was seen in preclinical models. So far this was not found in treated Duchenne patients.

Authors also mention examples of RNase H ASOs, where a gene transcript is cleaved so that less protein is produced. They then introduce mRNA therapy, where a messenger RNA is introduced to be translated into a (missing) protein. We all know this from the COVID-19 vaccines. However, for genetic diseases, the mRNA of a missing protein would be provided to the target tissue. This mRNA has to be modified to avoid an inflammatory response. Delivery is so far with lipid nanoparticles, which works for the liver after intravenous treatment.

Authors again focus on CF, where the mRNA and the nanoparticles have to be nebulized for delivery to the lung. Also this is still in the preclinical stage for CF and liver diseases. The challenge with mRNA therapy is that mRNA is transiently present, so repeated treatment is needed.

When proteins are missing, delivering a gene with viral vectors (e.g. AAV) is another option. However, AAV has only a limited capacity, can exacerbate liver pathology and cannot be used in patients with preexisting immunity. So alternative approaches will be needed. Authors end with the message that while a lot of progress has been made with ASOs and mRNA therapies, there is also still a very long way to go. I agree. The review is not bad, but it was not what I expected, as the focus on CF was not mentioned in the title.