What Can RNA-Based Therapy Do for Monogenic Diseases?

Abstract

The use of RNA-based approaches to treat monogenic diseases (i.e., hereditary disorders caused by mutations in single genes) has been developed on different fronts. One approach uses small antisense oligonucleotides (ASOs) to modulate RNA processing at various stages; namely, to enhance correct splicing, to stimulate exon skipping (to exclude premature termination codon variants), to avoid undesired messenger RNA (mRNA) transcript degradation via the nonsense-mediated decay (NMD) pathway, or to induce mRNA degradation where they encode toxic proteins (e.g., in dominant diseases). Another approach consists in administering mRNA, which, like gene therapy, is a mutation-agnostic approach with potential application to any recessive monogenic disease. This is simpler than gene therapy because instead of requiring targeting of the nucleus, the mRNA only needs to be delivered to the cytoplasm. Although very promising (as demonstrated by COVID-19 vaccines), these approaches still have potential for optimisation, namely regarding delivery efficiency, adverse drug reactions and toxicity.

A programmable dual-targeting di-valent siRNA scaffold supports potent multi-gene modulation in the central nervous system

“…Traditionally, oligonucleotide therapeutics have been applied to disorders where a single gene causes the disease (38). However, it has become increasingly clear that, for some monogenetic disorders, pathogenesis or progression is associated with multiple pathways (13).…”

The Platform Technology Approach to mRNA Product Development and Regulation

“…Several mRNA-LNP therapeutics are under clinical development [63][64][65][66][67][68][69] including oncology immune-therapeutics for a range of cancers including melanoma and other skin cancers, lung, cervical, breast and ovarian cancers, liver and gastric cancers, pancreatic cancer, bladder cancer, prostate and head and neck cancers. mRNA protein replacement therapeutics are being developed for a range of genetic diseases including cystic fibrosis and rare metabolic diseases, type 2 diabetes, cardiovascular disease and other fibroses.…”

The Platform Technology Approach to mRNA Product Development and Regulation

“…Several mRNA-LNP therapeutics are under clinical development [23,[85][86][87][88][89][90], including oncology immune-therapeutics for a range of cancers including melanoma and other skin cancers, lung, cervical, breast, and ovarian cancers, liver and gastric cancers, pancreatic cancer, bladder cancer, prostate cancer, and head and neck cancers. mRNA protein replacement therapeutics are being developed for a range of genetic diseases including cystic fibrosis and rare metabolic diseases, type 2 diabetes, cardiovascular disease, and other fibroses [91,92].…”

“…Some oncology trials, e.g., of individualised neoantigen therapies take advantage of the ability to rapidly synthesise mRNA sequences specific for individual patients. A number of other mRNA products also target diseases for which there are either no effective therapies or inadequate vaccines, including HIV, TB, malaria, cytomegalovirus, Zika, Nipah, and Lyme, as well as rare metabolic diseases [20][21][22][23][24][25][26][27][28].…”