<i>In silico</i>and<i>in vitro</i>evaluation of exonic and intronic off-target effects form a critical element of therapeutic ASO gapmer optimization

Kamola, Piotr J.; Kitson, Jeremy; Turner, Gemma F.; Maratou, Klio; Eriksson, Sofie; Panjwani, Aliza A.; Warnock, Linda C.; Guilloux, Gaelle A. Douillard; Moores, Kitty; Koppe, Emma; Wixted, William E.; Wilson, P. David; Gooderham, Nigel J.; Gant, Timothy W.; Clark, Kenneth L.; Hughes, Stephen A.; Edbrooke, Mark R.; Parry, Joel D.

doi:10.1093/nar/gkv857

Cited by 93 publications

(88 citation statements)

References 46 publications

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“…The risk of toxicity seems to apply equally to LNA and cEt, despite previous reports to the contrary, and is sequence-dependent. In the past year, three groups independently demonstrated that LNA and cEt gapmer ASOs induce liver toxicity by directing off-target RNase H cleavage of mismatched transcripts, particularly within introns 42-44 . Armed with this information, computational methods can be used to select ASOs with minimal complementarity to off-target transcripts (including introns).…”

Section: Chemical Evolution Of Asosmentioning

confidence: 99%

The chemical evolution of oligonucleotide therapies of clinical utility

2017

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After nearly 40 years of development, oligonucleotide therapeutics are nearing meaningful clinical productivity. One of the key advantages of oligonucleotide drugs is that their delivery and potency properties are derived primarily from the chemical structure of the oligonucleotide, while their target is defined by the base sequence. Thus, as oligonucleotides with a particular chemical design demonstrate appropriate distribution and safety profiles for clinical gene silencing in a particular tissue, this will open the door to the rapid development of additional drugs targeting other disease-associated genes in the same tissue. To achieve clinical productivity, the chemical architecture of the oligonucleotide needs to be optimized as a whole, using a combination of sugar, backbone, nucleobase and 3′/5′-terminal modifications. A portfolio of chemistries can be used to confer drug like properties onto the oligonucleotide as a whole, with minor chemical changes often translating into major improvements in clinical efficacy. Outstanding challenges in oligonucleotide chemical development include optimization of chemical architectures to ensure long-term safety and to enable robust clinical activity beyond the liver.

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Section: Chemical Evolution Of Asosmentioning

confidence: 99%

The chemical evolution of oligonucleotide therapies of clinical utility

2017

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“…For human clinical candidates, each ASO is screened in silico against the human genome and “hits” with 1, 2, or 3 mismatches are empirically tested for ASO-mediated changes of these mRNAs (Kamola et al, 2015; Monia et al, 1992). Thus, ASOs with potential overlap can be routinely screened against.…”

Section: Challenges For Antisense Applicationmentioning

confidence: 99%

Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases

Schoch

Miller

2017

Neuron

234

254

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Multiple neurodegenerative diseases are characterized by single protein dysfunction and aggregation. Treatment strategies for these diseases have often targeted downstream pathways to ameliorate consequences of protein dysfunction; however, targeting the source of that dysfunction, the affected protein itself, seems most judicious to achieve a highly effective therapeutic outcome. Antisense oligonucleotides (ASOs) are small sequences of DNA able to target RNA transcripts resulting in reduced or modified protein expression. ASOs are ideal candidates for the treatment of neurodegenerative diseases given numerous advancements made to their chemical modifications and delivery methods. Successes achieved in both animal models and human clinical trials have proven ASOs both safe and effective. With proper considerations in mind regarding the human applicability of ASOs, we anticipate ongoing in vivo research and clinical trial development of ASOs for the treatment of neurodegenerative diseases.

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“…Cell uptake, intracellular trafficking, and localization may differ across AON molecules and explain some of the observed diversity. Similar to putative mechanisms in the liver, AONs may interact with critical intracellular proteins to disrupt their function 8 or may hybridize to unintended transcripts with a detrimental impact on pathways involved with cell maintenance 9, 10. The lack of in vitro models that mimic the in vivo toxicity of AONs has considerably limited the mechanistic understanding of the effect of these compounds at a cellular level.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of EGF Uptake by Nephrotoxic Antisense Drugs In Vitro and Implications for Preclinical Safety Profiling

Moisan

Gubler

Zhang

et al. 2017

Molecular Therapy - Nucleic Acids

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Antisense oligonucleotide (AON) therapeutics offer new avenues to pursue clinically relevant targets inaccessible with other technologies. Advances in improving AON affinity and stability by incorporation of high affinity nucleotides, such as locked nucleic acids (LNA), have sometimes been stifled by safety liabilities related to their accumulation in the kidney tubule. In an attempt to predict and understand the mechanisms of LNA-AON-induced renal tubular toxicity, we established human cell models that recapitulate in vivo behavior of pre-clinically and clinically unfavorable LNA-AON drug candidates. We identified elevation of extracellular epidermal growth factor (EGF) as a robust and sensitive in vitro biomarker of LNA-AON-induced cytotoxicity in human kidney tubule epithelial cells. We report the time-dependent negative regulation of EGF uptake and EGF receptor (EGFR) signaling by toxic but not innocuous LNA-AONs and revealed the importance of EGFR signaling in LNA-AON-mediated decrease in cellular activity. The robust EGF-based in vitro safety profiling of LNA-AON drug candidates presented here, together with a better understanding of the underlying molecular mechanisms, constitutes a significant step toward developing safer antisense therapeutics.

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In silicoandin vitroevaluation of exonic and intronic off-target effects form a critical element of therapeutic ASO gapmer optimization

Cited by 93 publications

References 46 publications

The chemical evolution of oligonucleotide therapies of clinical utility

The chemical evolution of oligonucleotide therapies of clinical utility

Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases

Inhibition of EGF Uptake by Nephrotoxic Antisense Drugs In Vitro and Implications for Preclinical Safety Profiling

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