Towards Personalized Allele-Specific Antisense Oligonucleotide Therapies for Toxic Gain-of-Function Neurodegenerative Diseases
Abstract
:1. Introduction
2. Antisense Oligonucleotides
3. Backbone Modifications
4. Sugar Modifications
5. Base Modifications
6. Selective vs. Non-Selective Targeting Strategies
7. SNP-Based Allele-Specific Treatment Strategies
8. Target-Based ASO Design
9. The Challenge of Readout
10. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Modification | Tm per Nucleotide | References | Specific | General |
---|---|---|---|---|
Backbone | ||||
Phosphorothioate (PS) | 0.45 to 1 °C | [27,34,35,36,37,38,39] |
|
|
Mesylphosphoramidate (MsPA) | 1.3 to +1.1 °C (with respect to PS) | [39,40] |
| |
Phosphoryl guanidines (PG) | 1.2 to 0 °C | [41,42,43,44] |
| |
Sugar | ||||
Locked nucleic acids (LNA) | +1.5 to +9.1 °C | [27,45,46,47,48,49,50,51] |
|
|
2’O-methyl (2’-OMe) | 0 to +1.3 °C | [27,34,38,46] | ||
2’-O-methoxyethyl (2’-MOE) | +0.9 to +1.9 °C | [34,46,51,52,53] |
| |
2’4’-constrained 2’-O-ethyl (2’-cEt) | +4.7 to +6.1 °C | [51,54] |
| |
2’-O,4’-C-ethylene-bridged nucleic acid (ENA) | +5.2 °C | [49] |
| |
Base | ||||
G-clamp | +4 to +18 °C | [46,55,56] |
|
|
C5-propyne C | +1.5 to 1.6 °C | [55,57,58,59] |
| |
C5-propyne T | +0.9 to +2.6 °C | [34,54,55,57,58,59] |
| |
2-thio-thymidine | +0.3 to +1.8 °C | [54,60] |
| |
5’-thiazole analogues | +1.7 to 2.2 °C | [58,59] |
| |
5-Methyl cytosine | 0 to +1.1 °C | [25,34] |
Disease 1 Target | Cellular Function | ASO | Phase | ASO Type/Modifications | Ref./Clinical Trial |
---|---|---|---|---|---|
HD–HTT | Brain development, involved in vesicle trafficking and recycling, cell division, ciliogenesis, autophagy, development [107] | Tominersen, IONIS-HTTRx | Phase III halted (03/21) | Non-allele-specific, PS 2′-MOE | [2,84,108] NCT03842969 |
HD–HTT | WVE-003 (WVE-120101 & 120102: suspended) | Phase I/II | Allele-specific, PS stereopure | [2,72,109] NCT05032196 | |
ALS/FTD–FUS | DNA/RNA metabolism [110] | Jacifusen/ION36 | Phase III | Mutation-specific (p.P525L), PS 2′-MOE | [111,112,113] NCT04768972 |
ALS–SOD1 | Antioxidant [114] | Tofersen/IONIS-SOD1Rx (BIIB067) | Phase III | Non-allele-specific, PS 2′-MOE | [115,116] NCT02623699 NCT03070119 |
ALS/FTD–C9ORF72 | Repeat in noncoding region [117] | IONIS-C9Rx (BIIB078) | Phase I discontinued (03/22) | Non-allele specific, PS 2′-MOE | NCT03626012 NCT04288856 |
ALS/FTD–C9ORF72 | WVE004 | Phase I/II | Allele-specific (Targeting V1 and V3 transcript), PS PG stereopure | [118,119] NCT04931862 | |
ALS/SCA2–ATXN2 | RNA metabolism [120] | ION541 (BIIB105) | Phase I/II | PS 2′-MOE | [83,121] NCT04494256 |
AD/FTD–MAPT (TAU) | Stabilizing & promotion of microtubule assembly [122] | IONIS-MAPTRx (BIIB080) | Phase II | PS 2′-MOE | [123] |
SCA3–ATXN3 | Deubiquitinase [120] | ION260 (BIIB132) | Phase I | Non-allele-specific, PS 2′-MOE | [100,121] NCT05160558 |
PD–LRRK2 | Kinase involved in lysosomal processes, autophagy, mitophagy, vesicle trafficking [124] | ION859 (BIIB094) | Phase I/II | PS 2′-MOE | [125] NCT03976349 |
PD–SNCA | Presynaptic protein, involved in SNARE complex assembly [126] | ION464 (BIIB101) | Phase II | PS 2′-MOE | [127] NCT04165486 |
Alexander disease–GFAP | Intermediate filament [128] | Zilganersen, ION373 | Phase II | Non-allele-specific, PS 2′-MOE | [129] NCT04849741 CAS2305355-56-8 |
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Helm, J.; Schöls, L.; Hauser, S. Towards Personalized Allele-Specific Antisense Oligonucleotide Therapies for Toxic Gain-of-Function Neurodegenerative Diseases. Pharmaceutics 2022, 14, 1708. https://doi.org/10.3390/pharmaceutics14081708
Helm J, Schöls L, Hauser S. Towards Personalized Allele-Specific Antisense Oligonucleotide Therapies for Toxic Gain-of-Function Neurodegenerative Diseases. Pharmaceutics. 2022; 14(8):1708. https://doi.org/10.3390/pharmaceutics14081708
Chicago/Turabian StyleHelm, Jacob, Ludger Schöls, and Stefan Hauser. 2022. "Towards Personalized Allele-Specific Antisense Oligonucleotide Therapies for Toxic Gain-of-Function Neurodegenerative Diseases" Pharmaceutics 14, no. 8: 1708. https://doi.org/10.3390/pharmaceutics14081708
APA StyleHelm, J., Schöls, L., & Hauser, S. (2022). Towards Personalized Allele-Specific Antisense Oligonucleotide Therapies for Toxic Gain-of-Function Neurodegenerative Diseases. Pharmaceutics, 14(8), 1708. https://doi.org/10.3390/pharmaceutics14081708