RNA therapies are delivering as therapies for neuromuscular dystrophy patients: Editorial for the special issue on RNA therapies in Journal of Neuromuscular Diseases

It is our pleasure to welcome the reader to this special issue of JND dedicated to research and development of RNA therapies for patients with neuromuscular diseases (NMD). The field of RNA therapy is one of ever increasing modalities, but in the NMD field so far the focus has been on the antisense approach, which can be utilized to decrease the production of toxic proteins via activation of RNase H or initiating the RNA-induced silencing complex (RISC) mediated cleavage, or to restore/increase production of proteins through splicing modulation.

The splice modulators eteplirsen and nusinersen, were the first antisense oligonucleotides (ASOs) to be approved for NMDs in 2016, for Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), respectively. ¹ Almost a decade post approval, the guest editors of this special issue reflect on the differences between the target product profiles of these two compounds in a historical review, and outline how we can learn from this going forward. ²

One of the lessons learned is that delivery of ASOs and siRNA to skeletal muscle is challenging due to its abundance, and its nature: one has to treat not one organ, but hundreds of different muscles. After systemic delivery of ASOs and siRNAs, the target organs normally are the liver and the kidney. Muscle pathology can facilitate uptake to some extent, but generally efficiency of ASO delivery to skeletal muscle after systemic treatment is very limited. The review by Arechavala-Gomeza et al. highlights the different approaches that are currently under development to improve skeletal muscle delivery. ³ The review focuses on approaches that are currently tested in clinical trials, highlighting also that now all approaches work out or are safe and some clinical developments were stopped. Furthermore, the review highlights the versatility of the antisense approach, with clinical trials ongoing for splice modulating ASO for DMD, and for RNase H ASOs and siRNAs for facioscapulohumeral muscular dystrophy (FSHD) and myotonic dystrophy (DM1).

There is increasing evidence that NMDs are multisystemic diseases, affecting skeletal muscles and/or neuromuscular junctions, but often also other tissues, such as the heart and the central nervous system. Sometimes systemic treatment can result in effects on both skeletal muscle and heart, as it is outlined in the research paper by Iff, et al.. ⁴ There authors performed a retrospective analysis comparing patients treated with eteplisrsen with natural history controls, suggesting a protective effect on cardiac function in the treated individuals.

Many DMD patients also experience brain comorbidities due to the absence of one or more dystrophin isoforms, which play a role in central nervous system development. It has been shown that postnatal recovery of dystrophin can improve behavioral problems in the mdx mouse model for DMD, ⁵ showing that the pathology is likely a combination of developmental and maintenance components. Vacca et al., give a summary on the approaches that are being studied to improve delivery of RNA therapies to both the muscle and the central nervous system in model systems for DMD. ⁶

Of all approved RNA therapies, nusinersen has probably made the largest impact, with over 14,000 SMA patients treated and patients achieving milestones they would normally, by definition, not achieve. Matesanz et al. summarize the real-world evidence of nusinersen treatment. ⁷ While this report flags the impact that the treatment has made on the lives of individuals living with SMA, authors also stress that further research is needed as not all patients respond equally. Additionally, with treatment a new phenotype of SMA patients has arisen. Furthermore, more optimization is ongoing to test higher doses of nusinersen, as well as a chemically modified version with a slightly modified sequence, salanersen, in clinical trials, where a single annual dose would suffice. ⁸

As such we have come full circle, showing the opportunities RNA therapies offer for NMD patients, but also flagging that drug development does not stop after an approved treatment. Due to ongoing research in RNA therapy chemistry, further optimization can be achieved with better therapeutic effects and/or better treatment regimen.

General information

AAR discloses being employed by LUMC which has patents on exon skipping technology, some of which has been licensed to BioMarin and subsequently sublicensed to Sarepta. As co-inventor of some of these patents AAR was entitled to a share of royalties. AAR further discloses being ad hoc consultant for PTC Therapeutics, Sarepta Therapeutics, Regenxbio, Dyne Therapeutics, Lilly, BioMarin Pharmaceuticals Inc., Eisai, Entrada, Takeda, Splicesense, Galapagos, Sapreme, Italfarmaco and Astra Zeneca. AAR also reports being a member of the scientific advisory boards of Hybridize Therapeutics (past), Silence Therapeutics, Sarepta therapeutics, Sapreme and Mitorx. Remuneration for consulting and advising activities is paid to LUMC. In the past 5 years, LUMC also received speaker honoraria from Alnylam Netherlands, Italfarmaco and Pfizer and funding for contract research from Sapreme, Eisai, BioMarin, Galapagos and Synaffix. Project funding is received from Sarepta Therapeutics and Entrada via unrestricted grants. Again, for the past 5 years, ST has disclosed being employed by NCNP, which has patents on exon skipping technology and drugs. As a co-inventor of some of these patents, ST was also entitled to a share of royalties. ST further discloses being an ad hoc consultant for Nippon Shinyaku, Taiho, and Daiichi-Sankyo. ST also reports being a member of the scientific advisory boards of Nippon Shinyaku. ST received speaker honoraria from Nippon Shinyaku, Chugai, and project funding from Taiho.