Antisense oligonucleotides targeting the miR-29b binding site in the <i>GRN</i> mRNA increase progranulin translation

Aggarwal, Geetika; Banerjee, Subhashis; Jones, Spencer A.; Pavlack, Monica D.; Benchaar, Yousri; Bélanger, J.; Sévigny, Myriam; Smith, Denise M.; Niehoff, Michael L.; Vera, Ian Mitchelle S. de; Petkau, Terri L.; Leavitt, Blair R.; Jafar‐Nejad, Paymaan; Rigo, Frank; Morley, John E.; Farr, Susan A.; Dutchak, Paul A.; Sephton, Chantelle F.; Nguyen, Andrew D.

doi:10.1101/2022.01.12.476053

Cited by 4 publications

(5 citation statements)

References 55 publications

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“…For example, an 18-mer ASO targeting an intronic splicing silencer increased the inclusion of exon 7 of SMN2 in a humanized mouse model of spinal muscular atrophy [32]. Additionally, we recently showed that an 18-mer ASO that blocks a miR binding site in the GRN mRNA increases progranulin protein levels in a humanized mouse model [33]. Nonetheless, future studies could test ASOs of different lengths, such as 20-mers, targeting this same EJC region of the Grn R493X mRNA.…”

Section: Plos Onementioning

confidence: 97%

“…These results further suggest that alternative strategies should be pursued for increasing progranulin levels in the context of progranulin-deficient FTD. One such potential strategy is to use ASOs to block miR binding sites, such as miR-659 and miR-29b [35][36][37][38], in the 3' UTR of the GRN mRNA [33]. A notable advantage of this miR-targeting strategy is that it is agnostic to the specific disease mutation and could be used in the context of any of the >70 FTD-associated GRN mutations that have been identified [15].…”

Section: Plos Onementioning

confidence: 99%

See 1 more Smart Citation

Targeting nonsense-mediated RNA decay does not increase progranulin levels in the Grn R493X mouse model of frontotemporal dementia

Smith¹,

Niehoff²,

Jafar‐Nejad³

et al. 2023

PLoS ONE

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A common cause of frontotemporal dementia (FTD) are nonsense mutations in the progranulin (GRN) gene. Because nonsense mutations activate the nonsense-mediated RNA decay (NMD) pathway, we sought to inhibit this RNA turnover pathway as a means to increase progranulin levels. Using a knock-in mouse model harboring a common patient mutation, we tested whether either pharmacological or genetic inhibition of NMD upregulates progranulin in these GrnR493X mice. We first examined antisense oligonucleotides (ASOs) targeting an exonic region in GrnR493X mRNA predicted to block its degradation by NMD. As we previously reported, these ASOs effectively increased GrnR493X mRNA levels in fibroblasts in vitro. However, following CNS delivery, we found that none of the 8 ASOs we tested increased Grn mRNA levels in the brains of GrnR493X mice. This result was obtained despite broad ASO distribution in the brain. An ASO targeting a different mRNA was effective when administered in parallel to wild-type mice. As an independent approach to inhibit NMD, we examined the effect of loss of an NMD factor not required for embryonic viability: UPF3b. We found that while Upf3b deletion effectively perturbed NMD, it did not increase Grn mRNA levels in Grn+/R493X mouse brains. Together, our results suggest that the NMD-inhibition approaches that we used are likely not viable for increasing progranulin levels in individuals with FTD caused by nonsense GRN mutations. Thus, alternative approaches should be pursued.

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Section: Plos Onementioning

confidence: 97%

Section: Plos Onementioning

confidence: 99%

Targeting nonsense-mediated RNA decay does not increase progranulin levels in the Grn R493X mouse model of frontotemporal dementia

Smith¹,

Niehoff²,

Jafar‐Nejad³

et al. 2023

PLoS ONE

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show abstract

“…Steric blocking ASOs can also target regulatory sequences and structures in the untranslated regions (UTRs). This interaction can stabilize transcripts and increase target protein levels [75,76]. Finally, steric blocking ASOs can also be employed to prevent the translation of a transcript by the ribosomes, reducing protein levels [77,78].…”

Section: Aso Treatment Modalitiesmentioning

confidence: 99%

Treatability of the KMT2-Associated Neurodevelopmental Disorders Using Antisense Oligonucleotide-Based Treatments

Zardetto,

van Roon-Mom,

Aartsma-Rus

et al. 2024

Human Mutation

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Neurodevelopmental disorders (NDDs) of genetic origin are a group of early-onset neurological diseases with highly heterogeneous etiology and a symptomatic spectrum that includes intellectual disability, autism spectrum disorder, and learning and language disorders. One group of rare NDDs is associated with dysregulation of the KMT2 protein family. Members of this family share a common methyl transferase function and are involved in the etiology of rare haploinsufficiency disorders. For each of the KMT2 genes, at least one distinct disorder has been reported, yet clinical manifestations often overlap for multiple of these individually very rare disorders. Clinical care is currently focused on the management of symptoms with no targeted treatments available, illustrating a high unmet medical need and the urgency of developing disease-modifying therapeutic strategies. Antisense oligonucleotides (ASOs) are one option to treat some of these rare genetic disorders. ASOs are RNA-based treatments that can be employed to modulate gene expression through various mechanisms. In this work, we discuss the phenotypic features across the KMT2-associated NDDs and which ASO approaches are most suited for the treatment of each associated disorder. We hereby address variant-specific strategies as well as options applicable to larger groups of patients.

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“…This can be achieved through different mechanisms, such as skipping exons (including cryptic exons) and exon inclusion. ASOs are also able to influence protein levels by targeting the untranslated regions (UTRs) [16,17]. Here, the ASOs are not modifying splicing, but by sterically blocking regulatory elements, they can influence the stability of a transcript.…”

Section: Splice-switching Asosmentioning

confidence: 99%

Practical Recommendations for the Selection of Patients for Individualized Splice-Switching ASO-Based Treatments

Zardetto,

Lauffer,

van Roon-Mom

et al. 2024

Human Mutation

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Although around 6% of the world’s population is affected by rare diseases, only a small number of disease-modifying therapies are available. In recent years, antisense oligonucleotides (ASOs) have emerged as one option for the development of therapeutics for orphan diseases. In particular, ASOs can be utilized for individualized genetic treatments, addressing patients with a known disease-causing genetic variant, who would otherwise not be able to receive therapy. Careful prioritization of genetic variants amenable to an ASO approach is crucial to increase chances for successful treatments and reduce costs and time for drug development. At present, there is no consensus on how to systematically approach this selection procedure. Here, we present practical guidelines to evaluate disease-causing variants and standardize the process of selecting n-of-1 cases. We focus on variants leading to a loss of function in monogenic disorders and consider which splice-switching ASO-mediated treatments are applicable in each case. To ease the understanding and application of our guidelines, we created a hypothetical transcript covering different pathogenic variants and explained their evaluation in detail. We support our recommendations with real-life examples and add further considerations to be applied to specific cases to provide a comprehensive framework for selecting eligible variants.

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Antisense oligonucleotides targeting the miR-29b binding site in the GRN mRNA increase progranulin translation

Cited by 4 publications

References 55 publications

Targeting nonsense-mediated RNA decay does not increase progranulin levels in the Grn R493X mouse model of frontotemporal dementia

Targeting nonsense-mediated RNA decay does not increase progranulin levels in the Grn R493X mouse model of frontotemporal dementia

Treatability of the KMT2-Associated Neurodevelopmental Disorders Using Antisense Oligonucleotide-Based Treatments

Practical Recommendations for the Selection of Patients for Individualized Splice-Switching ASO-Based Treatments

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