Osteoarthritis (OA) is a debilitating degenerative joint disease that affects millions worldwide and yet current treatment procedures are ineffective. Abnormal activation of key signalling pathways, including canonical Wnt/β-catenin and Indian hedgehog (Ihh), could lead to OA development and progression.

This new research published in the Genes & Diseases journal by a team from the Chinese Academy of Sciences, Shenzhen University of Advanced Technology, Guangzhou International Bio Island, Guangxi Medical University, and the AO Research Institute explored whether silencing Ctnnb1 (encoding β-catenin) and Smo (Smoothened, a key component of the Ihh pathway) via CRISPR/CasRx could attenuate OA progression.

Initially, the researchers screened 20 CRISPR-derived RNAs (crRNAs) targeting Ctnnb1 and Smo and selected two optimal crRNAs for each gene. CasRx-mediated Ctnnb1 and Smo knockdown showed high efficiency and specificity without detectable off-target effects in vitro. The researchers then performed intra-articular injection of selected crRNAs driven by the adeno-associated virus (AAV) into a destabilization of medial meniscus (DMM)-induced OA mouse model. Interestingly, knockdown of either Ctnnb1 or Smo alone did not yield significant therapeutic effects.

However, further investigations revealed that when Ctnnb1 and Smo were silenced simultaneously, the CasRx system effectively mitigated joint structure degeneration associated with OA progression. Collectively, this study ascertains that intra-articular RNA editing, targeting both Ctnnb1 and Smo exerts its positive influence on diverse joint tissues, thereby modulating downstream signaling pathways and changing the course of OA progression.

In conclusion, this study highlights the potential of CRISPR/CasRx to concurrently target Wnt/β-catenin and Ihh signaling to alleviate OA progression. Overall, the findings of this research suggest that a dual-gene targeting strategy could pave the way for RNA-based gene therapies in OA management.

Reference

Title of Original Paper: CRISPR/CasRx-mediated RNA knockdown targeting β-catenin and Ihh signaling alleviates osteoarthritis

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2024.101468

Funding Information:

The National Key Research and Development Program of China (No. 2022YFA1207500)
The National Natural Science Foundation of China (No. 82394445, 82250710174, 82161160342, 82030067)
The Research Grants Council (RGC) of Hong Kong, China (No. HKU-17101821)
The Shenzhen Science and Technology Research Funding (China) (No. JSGGKQTD20210831174330015).

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus CiteScore: 7.3 | Impact Factor: 6.9

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