Limits...
Oligonucleotide Therapies: The Past and the Present.

Lundin KE, Gissberg O, Smith CI - Hum. Gene Ther. (2015)

Bottom Line: The various biological processes that have been targeted and the corresponding ON interventions found in the literature are discussed together with brief updates on some of the more recent developments.Similar to other novel medicines, the path to success has been lined with numerous failures, where different therapeutic ONs did not stand the test of time.However, there is room for cautious optimism.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge , Stockholm, Sweden .

ABSTRACT
In this review we address the development of oligonucleotide (ON) medicines from a historical perspective by listing the landmark discoveries in this field. The various biological processes that have been targeted and the corresponding ON interventions found in the literature are discussed together with brief updates on some of the more recent developments. Most ON therapies act through antisense mechanisms and are directed against various RNA species, as exemplified by gapmers, steric block ONs, antagomirs, small interfering RNAs (siRNAs), micro-RNA mimics, and splice switching ONs. However, ONs binding to Toll-like receptors and those forming aptamers have completely different modes of action. Similar to other novel medicines, the path to success has been lined with numerous failures, where different therapeutic ONs did not stand the test of time. Since the first ON drug was approved for clinical use in 1998, the therapeutic landscape has changed considerably, but many challenges remain until the expectations for this new form of medicine are met. However, there is room for cautious optimism.

No MeSH data available.


History of oligonucleotide therapeutics. Basic biology and chemistry with yellow background and clinical applications with coral red background. ON, oligonucleotide. The different chemical structures can be found in Supplementary Fig. S1 (Supplementary Data are available online at www.liebertpub.com/hum).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4554547&req=5

f1: History of oligonucleotide therapeutics. Basic biology and chemistry with yellow background and clinical applications with coral red background. ON, oligonucleotide. The different chemical structures can be found in Supplementary Fig. S1 (Supplementary Data are available online at www.liebertpub.com/hum).

Mentions: Two chemical modifications may be regarded as starting points for this field, namely, 2′-fluoro (2′-F) substitutions and phosphorothioate chemistry, since ONs with these modifications constitute versatile, synthetic analogs of the naturally occurring counterparts (Fig. 1). Thus, as described in one of the following sections, 2′-F substitutions are used in many synthetic ONs,3,4 since they increase binding affinity to the complementary target and also provide some protective effects. Also, the phosphorothioate chemistry, which was developed by Fritz Eckstein,5 remains a highly important modification for most of today's ON drugs, since it both confers protection against degradation and aids in the cellular uptake of ONs.6,7 In the 1960s another 2′ modification, 2′-O-methyl (2′-O-Me), was also synthesized in a laboratory for the first time.8 Although this nucleotide exists naturally in certain endogenous RNA species, it serves as an important ingredient in several synthetic, therapeutic ONs.


Oligonucleotide Therapies: The Past and the Present.

Lundin KE, Gissberg O, Smith CI - Hum. Gene Ther. (2015)

History of oligonucleotide therapeutics. Basic biology and chemistry with yellow background and clinical applications with coral red background. ON, oligonucleotide. The different chemical structures can be found in Supplementary Fig. S1 (Supplementary Data are available online at www.liebertpub.com/hum).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4554547&req=5

f1: History of oligonucleotide therapeutics. Basic biology and chemistry with yellow background and clinical applications with coral red background. ON, oligonucleotide. The different chemical structures can be found in Supplementary Fig. S1 (Supplementary Data are available online at www.liebertpub.com/hum).
Mentions: Two chemical modifications may be regarded as starting points for this field, namely, 2′-fluoro (2′-F) substitutions and phosphorothioate chemistry, since ONs with these modifications constitute versatile, synthetic analogs of the naturally occurring counterparts (Fig. 1). Thus, as described in one of the following sections, 2′-F substitutions are used in many synthetic ONs,3,4 since they increase binding affinity to the complementary target and also provide some protective effects. Also, the phosphorothioate chemistry, which was developed by Fritz Eckstein,5 remains a highly important modification for most of today's ON drugs, since it both confers protection against degradation and aids in the cellular uptake of ONs.6,7 In the 1960s another 2′ modification, 2′-O-methyl (2′-O-Me), was also synthesized in a laboratory for the first time.8 Although this nucleotide exists naturally in certain endogenous RNA species, it serves as an important ingredient in several synthetic, therapeutic ONs.

Bottom Line: The various biological processes that have been targeted and the corresponding ON interventions found in the literature are discussed together with brief updates on some of the more recent developments.Similar to other novel medicines, the path to success has been lined with numerous failures, where different therapeutic ONs did not stand the test of time.However, there is room for cautious optimism.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge , Stockholm, Sweden .

ABSTRACT
In this review we address the development of oligonucleotide (ON) medicines from a historical perspective by listing the landmark discoveries in this field. The various biological processes that have been targeted and the corresponding ON interventions found in the literature are discussed together with brief updates on some of the more recent developments. Most ON therapies act through antisense mechanisms and are directed against various RNA species, as exemplified by gapmers, steric block ONs, antagomirs, small interfering RNAs (siRNAs), micro-RNA mimics, and splice switching ONs. However, ONs binding to Toll-like receptors and those forming aptamers have completely different modes of action. Similar to other novel medicines, the path to success has been lined with numerous failures, where different therapeutic ONs did not stand the test of time. Since the first ON drug was approved for clinical use in 1998, the therapeutic landscape has changed considerably, but many challenges remain until the expectations for this new form of medicine are met. However, there is room for cautious optimism.

No MeSH data available.