Cellular uptake, tissue penetration, biodistribution, and biosafety of threose nucleic acids: Assessing in vitro and in vivo delivery

Wang, Fei; Liu, Ling Sum; Li, Pan; Lau, Cia-Hin; Leung, Hoi Man; Chin, Y. Rebecca; Tin, Chung; Lo, Pik Kwan

doi:10.1016/j.mtbio.2022.100299

Cited by 7 publications

(5 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although chemical modifications can improve plasma stability and protect against nuclease degradation, one of the primary obstacles to improving ASO’s efficiency at eliciting their intended effect at target cells is their poor intracellular delivery [ 4 ]. ASOs, when delivered on their own, typically enter cells through endocytosis, which involves the ASO being engulfed by the cell membrane, which subsequently buds off within the cell as an ASO-containing endosome [ 78 ].…”

Section: Antisense Oligonucleotidesmentioning

confidence: 99%

See 1 more Smart Citation

Potential of Cell-Penetrating Peptide-Conjugated Antisense Oligonucleotides for the Treatment of SMA

Leckie,

Yokota

2024

Molecules

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder that is caused by mutations in the survival motor neuron 1 (SMN1) gene, hindering the production of functional survival motor neuron (SMN) proteins. Antisense oligonucleotides (ASOs), a versatile DNA-like drug, are adept at binding to target RNA to prevent translation or promote alternative splicing. Nusinersen is an FDA-approved ASO for the treatment of SMA. It effectively promotes alternative splicing in pre-mRNA transcribed from the SMN2 gene, an analog of the SMN1 gene, to produce a greater amount of full-length SMN protein, to compensate for the loss of functional protein translated from SMN1. Despite its efficacy in ameliorating SMA symptoms, the cellular uptake of these ASOs is suboptimal, and their inability to penetrate the CNS necessitates invasive lumbar punctures. Cell-penetrating peptides (CPPs), which can be conjugated to ASOs, represent a promising approach to improve the efficiency of these treatments for SMA and have the potential to transverse the blood–brain barrier to circumvent the need for intrusive intrathecal injections and their associated adverse effects. This review provides a comprehensive analysis of ASO therapies, their application for the treatment of SMA, and the encouraging potential of CPPs as delivery systems to improve ASO uptake and overall efficiency.

show abstract

Section: Antisense Oligonucleotidesmentioning

confidence: 99%

“…While demonstrating efficacy in improving the SMA phenotype in treated patients, Nusinersen must be administered intrathecally for CNS delivery, accompanied by notable side effects [ 3 ]. Moreover, the inherent poor cellular uptake of ASOs limits their efficacy at lower doses [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Potential of Cell-Penetrating Peptide-Conjugated Antisense Oligonucleotides for the Treatment of SMA

Leckie,

Yokota

2024

Molecules

View full text Add to dashboard Cite

show abstract

“…36−39 Preclinical studies indicate that antisense oligonucleotides modified with TNA are potent and have low toxicity when assayed in cultured mammalian cells and animal models. 40 Here, we report a systematic evaluation of siRNAs modified with TNA, demonstrating that site-specific modification with TNA can increase the potency, duration of action, and safety of therapeutics that act through the RNAi pathway.…”

Section: ■ Introductionmentioning

confidence: 98%

“…TNA loops have been used to enhance the delivery and expression of linear DNA genes in eukaryotic cells, which is of relevance to gene therapy . TNA has also been explored as a chemical modality for antisense oligonucleotide therapeutics. − Preclinical studies indicate that antisense oligonucleotides modified with TNA are potent and have low toxicity when assayed in cultured mammalian cells and animal models . Here, we report a systematic evaluation of siRNAs modified with TNA, demonstrating that site-specific modification with TNA can increase the potency, duration of action, and safety of therapeutics that act through the RNAi pathway.…”

Section: Introductionmentioning

confidence: 99%

Shorter Is Better: The α-(l)-Threofuranosyl Nucleic Acid Modification Improves Stability, Potency, Safety, and Ago2 Binding and Mitigates Off-Target Effects of Small Interfering RNAs

Matsuda,

Bala,

Liao

et al. 2023

J. Am. Chem. Soc.

View full text Add to dashboard Cite

“…Aptamers based on the genetic polymer of threose nucleic acid (TNA), for example, remain functional in the presence of nucleases that rapidly degrade their natural DNA and RNA counterparts . This property, along with a high safety profile, − provides compelling evidence for TNA as a candidate genetic material for diagnostic and therapeutic applications that demand high biological stability.…”

Section: Introductionmentioning

confidence: 99%

Highly Parallelized Screening of Functionally Enhanced XNA Aptamers in Uniform Hydrogel Particles

et al. 2023

View full text Add to dashboard Cite

Xeno-nucleic acid (XNA) aptamers based on evolvable nonnatural genetic polymers hold enormous potential as future diagnostic and therapeutic agents. However, time-consuming and costly procedures requiring the purification of individual XNA sequences produced by largescale polymerase-mediated primer extension reactions pose a major bottleneck to the discovery of highly active XNA motifs for biomedical applications. Here, we describe a straightforward approach for rapidly surveying the binding properties of XNA aptamers identified by in vitro selection. Our strategy involves preparing XNA aptamer particles in which many copies of the same aptamer sequence are distributed throughout the gel matrix of a polyacrylamide-encapsulated magnetic particle. Aptamer particles are then screened by flow cytometry to assess target binding affinity and deduce structure−activity relationships. This generalizable and highly parallel assay dramatically accelerates the pace of secondary screening by allowing a single researcher to evaluate 48−96 sequences per day.

show abstract

Cellular uptake, tissue penetration, biodistribution, and biosafety of threose nucleic acids: Assessing in vitro and in vivo delivery

Cited by 7 publications

References 64 publications

Potential of Cell-Penetrating Peptide-Conjugated Antisense Oligonucleotides for the Treatment of SMA

Potential of Cell-Penetrating Peptide-Conjugated Antisense Oligonucleotides for the Treatment of SMA

Shorter Is Better: The α-(l)-Threofuranosyl Nucleic Acid Modification Improves Stability, Potency, Safety, and Ago2 Binding and Mitigates Off-Target Effects of Small Interfering RNAs

Highly Parallelized Screening of Functionally Enhanced XNA Aptamers in Uniform Hydrogel Particles

Contact Info

Product

Resources

About