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GeNeViSTA
Drug | Year of | Indication | Target | Tissue | Dosing | Results and conclusions |
approval |
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Fomivirsen | 1998 | CMV retinitis | CMV IE-2 (immediate early-2) | Eye | 300 μg every 4 weeks, intravitreal. | Clinical efficacy was witnessed but the drug marketing got hampered by dramatic decrease in CMV cases. |
Pegaptanib | 2004 | Neovascular Age related macular degeneration (AMD) | VEGF165 | Eye | 0.3 mg every 6 weeks, intravitreal | Clinical efficacy was present and no systemic toxicity was observed. Faced tough competition with ranibizumab and bevacizumab manufacturing companies. |
Mipomersen | 2013 | Homozygous familial hypercholesterolemia | ApoB-100 | Liver | 200 mg once weekly, subcuta-neous | Clinical efficacy was demonstrated but safety concerns were present. |
Defibrotide | 2016 | Hepatic veno-occlusive disease | Proteins, nonspecific | Liver | 6.25 mg/kg every 6 hours, i.v. infusion | Defibrotide demonstrated improved survival rate and complete response rate in phase III trial when compared with historical controls. |
Eteplirsen | 2016 | Duchenne muscular dystrophy | Dystrophin (Exon 51) | Muscle | 30 mg/kg once weekly, i.v. infusion | Controversy exists on the level of evidence demonstrating drug efficacy. The FDA approved the drug under conditional approval. In 2018, the EMA refused the approval of eteplirsen. |
Nusinersen | 2016 | Spinal muscular atrophy | SMN2 | CNS | 12 mg once every 4 months, Intrathe-cal | Profound clinical benefit of prolonged survival and improved motor function evident during interim analysis of two phase III studies. The FDA approved the drug based on the interim results. |
Inotersen | 2018 | Hereditary transthyretin amyloidosis | TTR | Liver | 300 mg once weekly, s.c. | Robust efficacy was demonstrated in a phase III study; however, two significant adverse events were observed during the study: thrombocytopenia causing death due to intracranial hemorrhage and renal dysfunction. |
Patisiran | 2018 | Hereditary transthyretin amyloidosis | TTR | Liver | 0.3 mg/kg or 30 mg based on BW, once every 3 weeks, i.v. infusion | The first approved siRNA. Robust efficacy was demonstrated in a phase III study with no safety concerns. |
SMA is an autosomal recessive neuromuscular disorder caused by a mutation in the SMN1 gene. Absence of functional SMN protein leads to degeneration of motor neurons in the spinal cord, resulting in progressive muscle weakness. SMN2 gene on chromosome 5q13 is identical to SMN1 except for a C-to-T transition within exon 7. This base substitution by disrupting a splicing enhancer or creating a splicing silencer, results in the exclusion of exon 7. SMN2, therefore produces only 10% properly spliced mRNA. The remaining 90% lack exon 7 and the resultant protein becomes unstable and is quickly degraded. Antisense oligonucleotide (Nusinersen) complementary to ISS-N1 (intronic splicing silencer) blocks its ability to exclude exon 7, resulting in full-length mRNA containing exon 7 (Figure 1).
In the interim analysis of clinical trial, 21 of 51 infants in the nusinersen group had a motor-milestone response as against 0 of 27 in control group (p<0.001), and this result prompted early termination of the trial (Finkel et al., 2018). The efficacy of nusinersen has also been observed in late onset SMA (Montes et al., 2019).
DMD is a fatal neuromuscular disorder caused by progressive muscle degeneration due to defective dystrophin protein. Eteplirsen functions by hybridizing to a site within exon 51, thereby blocking the splicing machinery from binding and forcing it to “skip” the exon. Exon 52 is spliced to exon 48, which restores the reading frame, generating a shortened but functional dystrophin (Figure 2). This is expected to benefit 14% of the entire DMD population.
USFDA approved the drug for DMD in 2016. However, it created a lot of controversies due to the lack of conclusive evidence regarding the efficacy of the drug. However, European Medical Agency (EMA) did not approve the drug stating that the study was done on only 12 patients with no control group and historical data was used for comparison. Following this, confirmatory phase 3 study using a larger sample size with a control group was performed.
The two major hurdles that hamper the widespread application of oligonucleotide therapeutics include drug safety and delivery.
Some oligonucleotides bind to Toll-like receptors and induce immune responses. Single-stranded phosphorothioate oligonucleotides are known for their renal accumulation causing glomerulonephritis in some individuals and a rare but notable reduction in platelet count (Crooke et al., 2017). Drug delivery also remains a significant challenge in ASO therapeutics because of its limitation in penetrating cell membrane due to their high molecular weight (5-15 kDa). Systemic delivery to most organs and tissues, with the exception of the liver, has proved to be exigent. All these observed effects can be minimized by the advent of newer versions of ASOs.
Emerging as a valid approach to selectively modulate gene expression, therapeutics with oligonucleotides has a great potential of being used as an ardent tool in drug designing. It has great potential in cancer therapeutics as well (Harada et al., 2019). The enhanced biological activity and efficient target delivery will pave the way for the apparently endless ASO therapeutic approaches in the near future.
1. Crooke, ST, et al. RNA-targeted therapeutics. Cell Metab. 2018; 27:714–739.
2. Crooke ST, et al. The effects of 2′-O-methoxyethyl containing antisense oligonucleotides on platelets in human clinical trials. Nucleic Acid Ther 2017; 27:121–129.
3. Davis S, et al. Potent inhibition of microRNA in vivo without degradation. Nucleic Acids Res 2009; 37:70–77.
4. Dias N, Stein CA. Antisense Oligonucleotides: Basic Concepts and Mechanisms. Mol Cancer Ther 2002; 1: 347–355.
5. Finkel RS, et al. Nusinersen versus Sham Control in Infantile Onset Spinal Muscular Atrophy. N Engl J Med. 2017; 377: 1723–1732.
6. Harada T, et al. Chemically Modified Antisense Oligonucleotide Against ARL4C Inhibits Primary and Metastatic Liver Tumor Growth. Mol Cancer Ther 2019; 18: 602–612.
7. Kurreck J. Antisense technologies. Improvement through novel chemical modifications. Eur J Biochem 2003; 270:1628–1644.
8. Montes J, et al. Nusinersen improves walking distance and reduces fatigue in later-onset spinal muscular atrophy. Muscle Nerve 2019; 60: 409–414.
9. Swayze EE, et al. Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals. Nucleic Acids Res 2007; 35: 687–700.
10. Vickers TA, et al. Fully modified 2’ MOE oligonucleotides redirect polyadenylation.Nucleic Acids Res 2001; 29:1293–1299.
11. Yin W. Targeting RNA: A Transformative Therapeutic Strategy. Clin Transl Sci 2019; 12: 98–112.
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