AUMskip™
Self-Delivering ASOs for Exon Skipping Applications
AUMskip™
Self-Delivering ASOs for Exon Skipping Applications
AUMskip™ is AUM Biotech's specialized antisense oligonucleotide product for exon skipping applications. These self-delivering ASOs are designed to bind pre-mRNA and redirect splicing, typically by causing a specific exon to be skipped (left out) during mRNA processing. By skipping a targeted exon, AUMskip oligos allow researchers to alter protein coding sequences or restore reading frames in cases of mutations, and to study the functional importance of exons.
Like AUMblock, AUMskip belongs to the steric-blocking category – it modulates RNA splicing through binding and blocking splice sites, without eliciting RNase H cleavage of the RNA. AUMskip oligos leverage the AUMsilence platform to achieve efficient delivery and potent activity in exon skipping assays, with no transfection reagents needed.
Precise Exon Skipping
AUMskip oligos are designed to target splice sites or splicing regulatory elements, causing the spliceosome to bypass specific exons during pre-mRNA processing. This results in the production of mRNAs lacking those exons, which can translate into truncated but potentially functional proteins.
Disease-Relevant Applications
Exon skipping is a proven strategy for addressing certain genetic diseases. For example, in Duchenne Muscular Dystrophy, skipping mutated exons can restore the reading frame of the dystrophin gene, allowing production of a shortened but partially functional protein. AUMskip enables research in this therapeutic area.
Self-Delivering to the Nucleus
AUMskip oligos are designed to efficiently enter cells without transfection reagents and localize to the nucleus, where pre-mRNA splicing occurs. This makes them ideal for targeting splicing events in primary cells, tissues, and in vivo models that are challenging to transfect with conventional methods.
AI-Optimized Splice Targeting
Our advanced AI-driven design algorithms analyze pre-mRNA sequences and structures to identify the most effective target sites for exon skipping. The system leverages known splicing motifs and accessibility predictions to create highly potent splice-modulating ASOs.
Mechanism of Action
Splice Site Blocking: After the AUMskip ASO is delivered into the nucleus of a cell, it binds to its pre-mRNA target at or near the exon one intends to skip. Common binding sites include the 3′ splice acceptor site, 5′ splice donor site, or splicing enhancer sequences.
Spliceosome Redirection: When the spliceosome assembles on the pre-mRNA, the bound AUMskip oligo sterically hinders the binding of splicing factors that normally recognize the exon's boundaries. Essentially, the ASO "hides" the exon from the splicing machinery.
Altered mRNA Production: As a consequence, the spliceosome skips over that exon, splicing together the flanking exons (e.g., exon N joined to exon N+2, leaving out exon N+1). The outcome is the production of an mRNA that is missing the targeted exon, resulting in a modified protein product.
Applications and Use Cases
Genetic Disease Research
AUMskip is valuable for research on diseases like Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA), where exon skipping strategies have therapeutic potential. Researchers can design customized AUMskip oligos for patient-specific mutations or for general disease models.
Alternative Splicing Research
If you want to study what an alternatively spliced exon does, you can use AUMskip to specifically exclude that exon from the mRNA pool and observe the effect on the cell. This is much faster than creating a knockout model lacking the exon, and it's reversible.
Protein Engineering
In some cases, skipping an exon can produce a desirable protein isoform. A researcher might intentionally skip an exon that encodes a domain to see how the truncated protein behaves. AUMskip allows generation of such isoforms without genetic engineering.
Gene Function Rescue
Exon skipping can sometimes rescue a gene's function by removing a problematic segment. For instance, if an exon contains a frame-shifting insertion, skipping that exon via AUMskip might restore the downstream reading frame and partially rescue expression.
AUMskip in Action - Select Published Studies
In a groundbreaking study on non-small cell lung cancer (NSCLC), researchers employed AUMskip™ sdASO™ to target the RNA-binding protein NOVA1, which regulates alternative splicing of human telomerase reverse transcriptase (hTERT). Using AUMskip™ oligos designed to modulate NOVA1 binding sites in the pre-mRNA of hTERT, scientists effectively altered the splicing pattern of hTERT transcripts, shifting from the full-length catalytically active form to inactive splice variants.
The study revealed that NOVA1 normally promotes the inclusion of exons in the reverse transcriptase domain of hTERT, resulting in the production of full-length transcripts essential for telomerase activity. After treatment with AUMskip™, RT-PCR analysis confirmed successful alteration of the splicing pattern, with a significant increase in the "minus beta" variant (skipping of exons 7 and 8), which introduces a frameshift and premature stop codon. This splicing shift resulted in progressively shortened telomeres, reduced cancer cell migration through extracellular matrices, and significantly smaller tumors in xenograft models.
Reference: Ludlow et al., Nature Communications, 2018. "NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer."
Ready to Modulate Splicing?
Order your custom AUMskip oligos today. Simply provide us with your gene and exon of interest, and our AI-powered design system will create optimized oligos for effective exon skipping. We offer personalized consultation to ensure your splicing modulation experiments achieve the desired results.
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