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Review
. 2024 Apr 23;7(1):489.
doi: 10.1038/s42003-024-06121-9.

Between hope and reality: treatment of genetic diseases through nucleic acid-based drugs

Virginie Baylot  1 , Thi Khanh Le  2 , David Taïeb  2 , Palma Rocchi  3 , Laurence Colleaux  2
Affiliations
Review

Between hope and reality: treatment of genetic diseases through nucleic acid-based drugs

Virginie Baylot et al. Commun Biol. .

Abstract

Rare diseases (RD) affect a small number of people compared to the general population and are mostly genetic in origin. The first clinical signs often appear at birth or in childhood, and patients endure high levels of pain and progressive loss of autonomy frequently associated with short life expectancy. Until recently, the low prevalence of RD and the gatekeeping delay in their diagnosis have long hampered research. The era of nucleic acid (NA)-based therapies has revolutionized the landscape of RD treatment and new hopes arise with the perspectives of disease-modifying drugs development as some NA-based therapies are now entering the clinical stage. Herein, we review NA-based drugs that were approved and are currently under investigation for the treatment of RD. We also discuss the recent structural improvements of NA-based therapeutics and delivery system, which overcome the main limitations in their market expansion and the current approaches that are developed to address the endosomal escape issue. We finally open the discussion on the ethical and societal issues that raise this new technology in terms of regulatory approval and sustainability of production.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. The main principal of gene replacement therapy using a viral vector.
Binding of Adeno-associated virus (AAV)-based vectors to specific membrane receptors (1) induces cellular internalization through endocytosis (2). Once inside the host cells, the viral vectors are released from the endosome (3) and shuttled into the nucleus, where the ssDNA is released (4) and undergoes second-strand synthesis to form double-stranded DNA. Subsequently, the transgene is transcribed into corresponding mRNAs (5) that will be translocated to the cytoplasm to generate therapeutic proteins (6). Created with BioRender.com (Agreement number : YC26MKZXYB).
Fig. 2
Fig. 2. siRNAs mechanism of action.
After the internalization of nanoparticles (1), siRNAs are released from the endosome (2) and loaded into the RNA-induced silencing complex (RISC) (3). The siRNAs are then incorporated into RISC, leading to the cleavage of the sense strand (4). The antisense strand (guide strand) binds to its target mRNA (5), and the siRNA guide strand bound to RNA induces an endonucleolytic cleavage mediated by the protein Argonaute-2 (Ago2), which prevents mRNA translation (6). Created with BioRender.com (Agreement number: ZF26ML06W7).
Fig. 3
Fig. 3. Main mechanisms of Antisense oligonucleotide (ASO).
(1) In RNase H-mediated RNA cleavage, heteroduplex formation between an ASO and an mRNA or pre-mRNA activates RNase-H, leading to mRNA/pre-mRNA degradation. (2) Steric hindrance based ASOs binding to mRNAs can disrupt the interaction of mRNAs with the 40S ribosomal subunit or interfere with their assembly on the 40S or 60S ribosomal subunits, resulting in translational arrest. (3) Splice-switching oligonucleotides or SSOs can modify gene expression by modulating pre-mRNA alternative splicing, resulting in exon inclusion or exon skipping. Created with BioRender.com (Agreement number : CO26ML0CXF).
Fig. 4
Fig. 4. The main principles of CRISPR/Cas9 genome editing.
CRISPR-associated nucleases (Cas proteins) are recruited to generate target-specific double-strand breaks (DSBs) through specific sequence recognition of the single guide RNA (sgRNA) with the target sequence of the genome and the presence of a protospacer-adjacent motif [PAM] sequence. DSBs are mainly repaired by endogenous repair pathways, including nonhomologous end joining (NHEJ) and homology-directed repair (HDR). NHEJ facilitates joining two DNA fragments without the need for exogenous homologous DNA, resulting in small random insertions or deletions at the cleavage site. Consequently, the expression of the target gene is disrupted due to the production of frameshift mutations or premature stop codons during NHEJ-based repair. On the other hand, HDR facilitates precise gene insertion or replacement through the presence of donor DNA that contains a desired sequence and sequence homology at the DSB site. Created with BioRender.com (Agreement number : MB26ML0B76).
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