214
The two most studied antisense oligonucleotides which belong to the second
generation are 2′-Methyl (2′-OMe) and 2′-Methoxyethyl (2′-MOE) modifications of
PS-modified antisense oligonucleotides. However, due to the inability of those molecules to induce an RNase-H mediated cleavage of target mRNAs, some chimeric
molecules of antisense oligonucleotides were synthesized in the aim to increase the
efficacy. An example of an antisense oligonucleotide, which belongs to this category and is approved in the market, is mipomersen. Peptide nucleic acid (PNA),
locked nucleic acid (LNA) and phosphorodiamidate (PMO) belong to the third generation of antisense oligonucleotides and they are the most studied antisense oligonucleotides of this category. This generation brought enhanced target affinity,
nuclease resistance, bioavailability, and pharmacokinetics. The structural difference
has to do with some chemical modifications of nucleotide’s furanose ring
(Penchovsky and Traykovska 2015; Chan et al. 2006; Kurreck 2003; Gleave and
Monia 2005).
The US Food and Drug Administration (FDA) approved antisense oligonucleotides for the treatment of a virus; the cytomegalovirus (CMV) induced chorioretinitis (Traykovska et al. 2018). Their approval gave hope for the treatment of other
pathogenic conditions in the future. Especially, the first antisense oligonucleotide,
which was approved for the market, was fomivirsen or vitravene, which is a firsteneration anti-CMV oligonucleotide. Fomivirsen is used for local application. Its
route of administration is intravitreal and it is distributed to retinal epithelium with
no significant systemic distribution. Macugen or Pegaptanib is another antisense
oligonucleotide that is approved by the FDA. It is used for the treatment of a leading
cause of blindness in adults above the age of 50 years, the age related macular
degeneration (AMD) of the retina. However, during the years, the drug’s use
decreased due to the existence of more effective drugs, ranibizumab and anti-VEGF
mAB bevacizumab, for the treatment of age related macular degeneration. Some
antisense oligonucleotides were approved for the treatment of neurological diseases
as Duchenne muscular dystrophy (DMD) and Spinal muscular atrophy (SMA).
DMD and Becker muscular dystrophy (BMD) are myopathies characterized by progressive muscle degeneration (Capitanio et al. 2020).
They are fatal X-linked genetic diseases with recessive inheritance. Becker muscular dystrophy is milder in comparison to Duchenne muscular dystrophy. The
severity of Duchenne muscular dystrophy is due to the complete absence of dystrophin production while in Becker muscular dystrophy dystrophin is produced but it
is abnormal or reduced. In Duchenne muscular dystrophy, the abnormal gene is
located in Xp21 locus and it is one of the largest genes. Some of the clinical manifestations involve muscle hypotonia, delay in motor skills and weakness of proximal muscles. In the later stages, the disease presents with skeletal deformities like
scoliosis, pharyngeal weakness, and contractions, which may involve the elbows,
knees, and Spinal muscular atrophy is a progressive autosomal recessive disease.
The pathogenesis involves a mutation in the survival motor neuron (SNM1) gene
that is located in the fifth chromosome and leads to a deficiency in survival motor
neuron protein. There are three types of SMA disease. Type I SMA either manifests
early or affects mostly the infants, which are born with the symptoms of the disease,
A. Valsamatzi-Panagiotou et al.
The two most studied antisense oligonucleotides which belong to the second
generation are 2′-Methyl (2′-OMe) and 2′-Methoxyethyl (2′-MOE) modifications of
PS-modified antisense oligonucleotides. However, due to the inability of those molecules to induce an RNase-H mediated cleavage of target mRNAs, some chimeric
molecules of antisense oligonucleotides were synthesized in the aim to increase the
efficacy. An example of an antisense oligonucleotide, which belongs to this category and is approved in the market, is mipomersen. Peptide nucleic acid (PNA),
locked nucleic acid (LNA) and phosphorodiamidate (PMO) belong to the third generation of antisense oligonucleotides and they are the most studied antisense oligonucleotides of this category. This generation brought enhanced target affinity,
nuclease resistance, bioavailability, and pharmacokinetics. The structural difference
has to do with some chemical modifications of nucleotide’s furanose ring
(Penchovsky and Traykovska 2015; Chan et al. 2006; Kurreck 2003; Gleave and
Monia 2005).
The US Food and Drug Administration (FDA) approved antisense oligonucleotides for the treatment of a virus; the cytomegalovirus (CMV) induced chorioretinitis (Traykovska et al. 2018). Their approval gave hope for the treatment of other
pathogenic conditions in the future. Especially, the first antisense oligonucleotide,
which was approved for the market, was fomivirsen or vitravene, which is a firsteneration anti-CMV oligonucleotide. Fomivirsen is used for local application. Its
route of administration is intravitreal and it is distributed to retinal epithelium with
no significant systemic distribution. Macugen or Pegaptanib is another antisense
oligonucleotide that is approved by the FDA. It is used for the treatment of a leading
cause of blindness in adults above the age of 50 years, the age related macular
degeneration (AMD) of the retina. However, during the years, the drug’s use
decreased due to the existence of more effective drugs, ranibizumab and anti-VEGF
mAB bevacizumab, for the treatment of age related macular degeneration. Some
antisense oligonucleotides were approved for the treatment of neurological diseases
as Duchenne muscular dystrophy (DMD) and Spinal muscular atrophy (SMA).
DMD and Becker muscular dystrophy (BMD) are myopathies characterized by progressive muscle degeneration (Capitanio et al. 2020).
They are fatal X-linked genetic diseases with recessive inheritance. Becker muscular dystrophy is milder in comparison to Duchenne muscular dystrophy. The
severity of Duchenne muscular dystrophy is due to the complete absence of dystrophin production while in Becker muscular dystrophy dystrophin is produced but it
is abnormal or reduced. In Duchenne muscular dystrophy, the abnormal gene is
located in Xp21 locus and it is one of the largest genes. Some of the clinical manifestations involve muscle hypotonia, delay in motor skills and weakness of proximal muscles. In the later stages, the disease presents with skeletal deformities like
scoliosis, pharyngeal weakness, and contractions, which may involve the elbows,
knees, and Spinal muscular atrophy is a progressive autosomal recessive disease.
The pathogenesis involves a mutation in the survival motor neuron (SNM1) gene
that is located in the fifth chromosome and leads to a deficiency in survival motor
neuron protein. There are three types of SMA disease. Type I SMA either manifests
early or affects mostly the infants, which are born with the symptoms of the disease,
A. Valsamatzi-Panagiotou et al.