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Scherman. Rare Dis Orphan Drugs J 2023;2:12 https://dx.doi.org/10.20517/rdodj.2023.01 Page 17 of 35

Table 2. Nusinersen and inotersen IUPAC formula
Nusinersen condensed IUPAC formula:
Thy-MeOEt(-2)Ribf-sP-m5Cyt-MeOEt(-2)Ribf-sP-Ade-MeOEt(-2)Ribf-sP-m5Cyt-MeOEt(-2)Ribf-sP-Thy-MeOEt(-2)Ribf-sP-Thy-MeOEt(-2)Ribf-sP-
Thy-MeOEt(-2)Ribf-sP-m5Cyt-MeOEt(-2)Ribf-sP-Ade-MeOEt(-2)Ribf-sP-Thy-MeOEt(-2)Ribf-sP-Ade-MeOEt(-2)Ribf-sP-Ade-MeOEt(-2)Ribf-sP-Thy-
MeOEt(-2)Ribf-sP-Gua-MeOEt(-2)Ribf-sP-m5Cyt-MeOEt(-2)Ribf-sP-Thy-MeOEt(-2)Ribf-sP-Gua-MeOEt(-2)Ribf-sP-Gua-MeOEt(-2)Ribf
Nusinersen detailed IUPAC formula:
O2'-(2-methoxyethyl)-5-methyl-P-thio-uridylyl-(3'- > 5')-O2'-(2-methoxyethyl)-5-methyl-P-thio-cytidylyl-(3'- > 5')-O2'-(2-methoxyethyl)-P-thio-
adenylyl-(3'- > 5')-O2'-(2-methoxyethyl)-5-methyl-P-thio-cytidylyl-(3'- > 5')-O2'-(2-methoxyethyl)-5-methyl-P-thio-uridylyl-(3'- > 5')-O2'-(2-
methoxyethyl)-5-methyl-P-thio-uridylyl-(3'- > 5')-O2'-(2-methoxyethyl)-5-methyl-P-thio-uridylyl-(3'- > 5')-O2'-(2-methoxyethyl)-5-methyl-P-thio-
cytidylyl-(3'- > 5')-O2'-(2-methoxyethyl)-P-thio-adenylyl-(3'- > 5')-O2'-(2-methoxyethyl)-5-methyl-P-thio-uridylyl-(3'- > 5')-O2'-(2-methoxyethyl)-P-
thio-adenylyl-(3'- > 5')-O2'-(2-methoxyethyl)-P-thio-adenylyl-(3'- > 5')-O2'-(2-methoxyethyl)-5-methyl-P-thio-uridylyl-(3'- > 5')-O2'-(2-
methoxyethyl)-P-thio-guanylyl-(3'- > 5')-O2'-(2-methoxyethyl)-5-methyl-P-thio-cytidylyl-(3'- > 5')-O2'-(2-methoxyethyl)-5-methyl-P-thio-uridylyl-
(3'->5')-O2'-(2-methoxyethyl)-P-thio-guanylyl-(3'- > 5')-O2'-(2-methoxyethyl)-guanosine
Inotersen compacted IUPAC formula:
Thy-MeOEt(-2)Ribf-sP-m5Cyt-MeOEt(-2)Ribf-sP-Thy-MeOEt(-2)Ribf-sP-Thy-MeOEt(-2)Ribf-sP-Gua-MeOEt(-2)Ribf-sP-dGuo-sP-dThd-sP-dThd-sP-
dAdo-sP-m5Cyt-dRibf-sP-dAdo-sP-dThd-sP-dGuo-sP-dAdo-sP-dAdo-sP-Ade-MeOEt(-2)Ribf-sP-Thy-MeOEt(-2)Ribf-sP-m5Cyt-MeOEt(-2)Ribf-sP-
m5Cyt-MeOEt(-2)Ribf-sP-m5Cyt-MeOEt(-2)Ribf

Figure 9. Summary of the genetic and molecular defects causing the several types of SMA severity and of treatment by a blocker ASO.
A: In non-affected individuals, both SMN1 and SMN2 genes are functional wild-type. SMN1 pre-mRNA is transcribed into a complete
mRNA corresponding to the 9 exons: 1,2a,2B,3,4,5, 6,7and 8. This leads to the production of a completely functional SMN1 protein,
which does not occur in SMA patients. B: The SMN2 paralog gene contains several sequences which negatively impact the correct
splicing and impair the incorporation of Exon 7 into the maturated SMN2 mRNA. The most important of these inhibitory sequences is
the intronic splicing silencer N1 (ISS N1) located in 5’ of Intron 7. Therefore, only a 10 to 20 % minority of SMN2 transcripts contain all
necessary exonic sequences for a functional SMN2 protein. From 80 to 90% of SMN2 transcripts are translated in a shortened non-
functional SMN2 protein devoid of Exon 7, which is unstable. The presence of multiple copies of the SMN2 gene results in a higher
quantity of functional SMN2 being produced and partially alleviates the disease severity. Type I patients generally possess 2 SMN2
copies, Type II having 3 SMN2 copies, and Type III and IV having 4 SMN2 gene copies. C: In SMA patients, a mutation/deletion induces
the loss of SMN1 protein production. An ASO designed as a steric blocker of ISS N1 is highly efficient in increasing the level of fully
competent SMN2 protein, and has been clinically validated as the Nusinersen drug.

closing itself, concomitantly with the expression in capillary endothelium of tight junctions and Glut1
glucose transporter. This suggested that the PS- 2’O-Me ASOs Nusinersen did not cross the blood-brain
barrier. However, direct Nusinersen administration into the cerebrospinal fluid or the brain parenchyma