Cell-Penetrating Peptide Conjugates of Steric Blocking Oligonucleotides as Therapeutics for Neuromuscular Diseases from a Historical Perspective to Current Prospects of Treatment

Abstract

The review starts with a historical perspective of the achievements of the Gait group in synthesis of oligo-nucleotides (ONs) and their peptide conjugates toward the award of the 2017 Oligonucleotide Therapeutic Society Lifetime Achievement Award. This acts as a prelude to the rewarding collaborative studies in the Gait and Wood research groups aimed toward the enhanced delivery of charge neutral ON drugs and the development of a series of Arg-rich cell-penetrating peptides called Pip (peptide nucleic acid/phosphorodiamidate morpholino oligonucleotide [PNA/PMO] internalization peptides) as conjugates of such ONs. In this review we concentrate on these developments toward the treatment of the neuromuscular diseases Duchenne muscular dystrophy and spinal muscular atrophy toward a platform technology for the enhancement of cellular and in vivo delivery suitable for widespread use as neuromuscular and neurodegenerative ON drugs.

“Betwixt Mine Eye and Heart a League Is Took”: The Progress of Induced Pluripotent Stem-Cell-Based Models of Dystrophin-Associated Cardiomyopathy

“…The use of these molecules for the treatment of DMD patients still remains controversial. Next-generation AONs are in development in order to improve their delivery and efficacy, e.g., adding short peptide sequences called “cell-penetrating peptides” or novel stereochemical modifications of the 2’OMe backbone proved to be positive alterations [ 226 , 227 ].…”

Increased Affinity of 2′‐O‐(2‐Methoxyethyl)‐Modified Oligonucleotides to RNA through Conjugation of Spermine at Cytidines

“…Solvents were then removed under reduced pressure to yield the final product: 609 mg, 93 % overall yield. 1 (12). Compound 11 (1.79 mmol, 1.17 g) was co-evaporated three times in dry acetonitrile (15 ml).…”

“…The drive to develop new structural modifications for oligonucleotides in industry and in academia continues, though priorities for medicinal chemists have changed in line with evolving challenges in the field. For instance, the development of carrier groups to deliver drugs more efficiently and to a wider range of tissues has become a major focus since the discovery that N ‐acetylgalactosamine (GalNac) conjugated groups are able to increase 100–1000‐fold delivery of siRNAs to hepatocytes . Also, the push for stereochemically‐pure PS drugs has been boosted by advances in phosphoramidite chemistry .…”

“…For instance, the development of carrier groups to deliver drugs more efficiently and to a wider range of tissues has become a major focus since the discovery that N-acetylgalactosamine (GalNac) conjugated groups are able to increase 100 -1000-fold delivery of siRNAs to hepatocytes. [10][11][12] Also, the push for stereochemically-pure PS drugs has been boosted by advances in phosphoramidite chemistry. [13] Both of these strategies are being applied to 2'-MOE-and LNA-oligonucleotides, since they may improve the pharmacokinetics properties and thereby show pharmacological activity in cell/tissue types where delivery is as yet limiting.…”

Progress in the molecular pathogenesis and nucleic acid therapeutics for Parkinson's disease in the precision medicine era

“…263 However, toxic effects, especially nephrotoxicity, remains as the main challenge to this category of peptide reaching clinical application. 264 Exosomes are endocytic nano-vesicles that could enter the CNS through transcytosis or internalization by endothelial cells 265 and thus have been designed as drug vehicles. 266 Several preclinical studies are using exosomes to deliver siRNAs for neurological diseases, including Huntington's disease 267 and glioblastoma multiforme with few toxic effects or immunogenicity observed after repeated doses.…”