Therapeutic Prospects of Exon Skipping for Epidermolysis Bullosa
Abstract
:1. Epidermolysis Bullosa
2. Exon Skipping
3. Antisense Oligonucleotides
4. ASOs Targeting Mutated Exons in Epidermolysis Bullosa
5. Lessons from Natural Exon Skipping in Epidermolysis Bullosa
6. Selection of Epidermolysis Bullosa Genes and Exons for Targeting with Exon Skipping
7. Development of ASOs for Targeting Exon Skipping in Epidermolysis Bullosa
8. Delivery of ASO Therapies
9. Concluding Remarks and Future Perspectives
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Level of Blistering | Gene | Protein | No. of Exons | In-Frame Exons | Percentage Skippable 1 | No. of ClinVar Variants 2 in Skippable Exons | Percentage Variants in Skippable Exons |
---|---|---|---|---|---|---|---|
Basal epidermal | KRT14 | Keratin 14 | 8 | 3 | 37.5 | 20 (39) | 51.3 |
KRT5 | Keratin 5 | 9 | 4 | 44.4 | 22 (24) | 45.8 | |
PLEC | Plectin | 39 | 17 | 43.6 | 43 (49) | 87.8 | |
KLHL24 | Kelch-like family member 24 | 6 | 2 | 33.3 | 0 (6) | 0.0 | |
EXPH5 | Exophilin 5 | 6 | 0 | 0.0 | 0 (1) | 0.0 | |
CD151 | Tetraspanin-24 | 7 | 5 | 71.4 | 2 (2) | 100.0 | |
DST | Dystonin | 24 | 11 | 45.8 | 22 (26) | 84.6 | |
Intralamina Lucida | COL17A1 | Type XVII Collagen | 55 | 53 | 96.4 | 37 (38) | 97.4 |
ITGB4 | Integrin β4 | 39 | 20 | 51.3 | 15 (28) | 53.6 | |
LAMA3 | Laminin α3 chain | 75 | 25 | 33.3 | 24 (72) | 33.3 | |
LAMB3 | Laminin β3 chain | 22 | 5 | 22.7 | 36 (108) | 33.3 | |
LAMC2 | Laminin γ2 chain | 23 | 9 | 39.1 | 29 (73) | 39.7 | |
ITGA6 | Integrin α6 | 25 | 10 | 40.0 | 2 (4) | 50.0 | |
ITGA3 | Integrin α3 | 25 | 10 | 40.0 | 2 (7) | 28.6 | |
Sublamina Densa | COL7A1 | Type VII Collagen | 118 | 107 | 90.7 | 270 (297) | 90.9 |
Mixed levels | FERMT1 | Kindlin-1 | 14 | 9 | 64.3 | 12 (24) | 50.0 |
Gene | Exon | ASO Sequence | GC% of ASO | ASO Length | Start Position 1 | Predicted Efficiency % 2 | ASO Chemistry 3 | ASO Name | Reference |
---|---|---|---|---|---|---|---|---|---|
COL7A1 | 10 | CGGGCCUCAGGCACCAAGUUC | 66 | 21 | 64 | 26.0 (2′OMe) | 2′-OMe-PS | H10A(+65+85) | [22] |
COL7A1 | 10 | CGGGCCUCAGGCACCAAGUUC | 66 | 21 | 64 | 7.7 (PMO) | PMO | H10A(+65+85) | [22] |
COL7A1 | 10 | CUUCCCCCGCACUGACCAGUCUC | 65 | 23 | N.A. 4 | 2′-OMe-PS | H10D(+07-16) | [22] | |
COL7A1 | 10 | CUUCCCCCGCACUGACCAGUCUC | 65 | 23 | N.A. 4 | PMO | H10D(+07-16) | [22] | |
COL7A1 | 70 | CGCACACUUCCAGGC | 66 | 15 | 32 | 8.3 (2′OMe) | 2′-OMe-PS | [27] | |
COL7A1 | 73 | CGUUCUCCAGGAAAGCCGAUG | 57 | 21 | 5 | 8.1 (2′OMe) 5 | 2′-MOE-PS | QR-313 | [17] |
COL7A1 | 73 | TCTTGCGCCCGACTTCCCGCTGGCACCTCT | 67 | 30 | 20 | 26.6 (2′OMe) | 2′OMe | [18] | |
COL7A1 | 73 | UUCAGCCCGCGUUCUCCAGG | 65 | 20 | 15 | 11.6 (2′OMe) | 2′-OMe-PS | H73A(+16+35) | [22] |
COL7A1 | 73 | UUCAGCCCGCGUUCUCCAGG | 65 | 20 | 15 | 22.6 (PMO) | PMO | H73A(+16+35) | [22] |
COL7A1 | 73 | CGCCCUUCAGCCCGCGUUCU | 70 | 20 | 20 | 21.3 (2′OMe) | 2′-OMe-PS | H73A(+21+40) | [22] |
COL7A1 | 73 | CGCCCUUCAGCCCGCGUUCU | 70 | 20 | 20 | 47.9 (PMO) | PMO | H73A(+21+40) | [22] |
COL7A1 | 73 | CGCCCUUCAGCCCGCGUUCUCCAGG | 72 | 25 | 15 | 49.9 (2′OMe) | 2′-OMe-PS | H73A(+16+40) | [22] |
COL7A1 | 73 | CGCCCUUCAGCCCGCGUUCUCCAGG | 72 | 25 | 15 | 60.0 (PMO) | PMO | H73A(+16+40) | [22] |
COL7A1 | 80 | TCCCAGACGTCCCAGGTTCTCCGG | 67 | 24 | N.A. 4 | 2′OMe | [18] | ||
COL7A1 | 105 | GAUACCAGGCACUCCAUCCU | 55 | 20 | 13 | 15.2 (2′OMe) | 2′OMe | AON1 | [16] |
COL7A1 | 105 | CAUGAAGCCAACAUCUCCUU | 45 | 20 | 43 | 11.3 (2′OMe) | 2′OMe | AON2 | [16] |
COL17A1 | 7 | TTTGACTCCGTCCTCTGGTT | 50 | 20 | 10 | 3.8 (2′OMe) | 2′-OMe-PS | AON1 | [19] |
COL17A1 | 7 | TCGTGTTTGACTCCGTCCTC | 55 | 20 | 15 | 11.7 (2′OMe) | 2′-OMe-PS | AON2 | [19] |
COL17A1 | 7 | CTCCGTCCTCTGGTTGAAGA | 55 | 20 | 5 | 42.4 (2′OMe) | 2′-OMe-PS | AON3 | [19] |
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Vermeer, F.C.; Bremer, J.; Sietsma, R.J.; Sandilands, A.; Hickerson, R.P.; Bolling, M.C.; Pasmooij, A.M.G.; Lemmink, H.H.; Swertz, M.A.; Knoers, N.V.A.M.; et al. Therapeutic Prospects of Exon Skipping for Epidermolysis Bullosa. Int. J. Mol. Sci. 2021, 22, 12222. https://doi.org/10.3390/ijms222212222
Vermeer FC, Bremer J, Sietsma RJ, Sandilands A, Hickerson RP, Bolling MC, Pasmooij AMG, Lemmink HH, Swertz MA, Knoers NVAM, et al. Therapeutic Prospects of Exon Skipping for Epidermolysis Bullosa. International Journal of Molecular Sciences. 2021; 22(22):12222. https://doi.org/10.3390/ijms222212222
Chicago/Turabian StyleVermeer, Franciscus C., Jeroen Bremer, Robert J. Sietsma, Aileen Sandilands, Robyn P. Hickerson, Marieke C. Bolling, Anna M.G. Pasmooij, Henny H. Lemmink, Morris A. Swertz, Nine V.A.M. Knoers, and et al. 2021. "Therapeutic Prospects of Exon Skipping for Epidermolysis Bullosa" International Journal of Molecular Sciences 22, no. 22: 12222. https://doi.org/10.3390/ijms222212222