Gene editing to improve joint function
Inventors
Millett, Peter J. • Russell, Iain Alasdair • Allen, Matthew J.
Assignees
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Publication Number
US-12419968-B2
Publication Date
2025-09-23
Expiration Date
Abstract
The present invention provides compositions and methods for treating joint disorders that are characterized by an inflammatory component. In some aspects, the compositions and methods are to prevent the progression of osteoarthritis and other arthritides and to treat osteoarthritis and other arthritides in a mammalian joint.
Core Innovation
The disclosure relates to gene-editing of inflammatory targets in synovial joint cells to improve joint function and to treat or prevent osteoarthritis/arthritides. The approach focuses on reducing cytokine expression, including IL-1α and IL-1β, in connection with an inflammatory component associated with joint disorders.
A therapeutically effective CRISPR gene-editing system is used, where the system comprises an mRNA encoding a CRISPR Associated Protein 9 (Cas9) protein and at least one guide RNA. The guide RNA targets an IL-1α gene or an IL-1β gene, and the guide RNA comprises a sequence complementary to a target sequence in exon 4 adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein.
Delivery to the joint is described using an AAV delivery system, including AAV serotypes and variants, or other carriers such as liposomes. In certain embodiments, administration is described as intra-articular injection into a joint and/or using a controlled-release hydrogel.
Claims Coverage
The provided independent claims are clm-00001 and clm-00011. Each independent claim is directed to a pharmaceutical composition for treatment or prevention of a joint disease or condition using a therapeutically effective CRISPR gene-editing system that includes mRNA encoding Cas9 and guide RNA targeting exon 4 of an IL-1 gene adjacent to a Cas9 PAM. Across the two independent claims, there are two distinct target cytokine genes with the same exon 4 and PAM-adjacent targeting concept.
CRISPR composition for treating or preventing a joint disease via IL-1α exon 4 targeting
A pharmaceutical composition for the treatment or prevention of a joint disease or condition comprising a therapeutically effective CRISPR gene-editing system with an mRNA encoding a Cas9 protein and at least one guide RNA targeting an IL-1α gene, where the guide RNA sequence is complementary to a target sequence in exon 4 of the IL-1α gene and the target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein.
CRISPR composition for treating or preventing a joint disease via IL-1β exon 4 targeting
A pharmaceutical composition for the treatment or prevention of a joint disease or condition comprising a therapeutically effective CRISPR gene-editing system with an mRNA encoding a Cas9 protein and at least one guide RNA targeting an IL-1β gene, where the guide RNA sequence is complementary to a target sequence in exon 4 of the IL-1β gene and the target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein.
The independent claim set provides coverage for pharmaceutical compositions that use an mRNA-encoded Cas9 and guide RNAs that target exon 4 of an IL-1 gene with the target sequence adjacent to a Cas9 PAM.
Stated Advantages
Improve joint function.
Treat or prevent osteoarthritis/arthritides.
Documented Applications
Treatment or prevention of a joint disease or condition associated with osteoarthritis/arthritides, directed at inflammatory cytokine expression using IL-1α or IL-1β gene editing.
Mouse osteoarthritis model assessments including IL-1 silencing, inflammation biomarkers, histopathology, and evaluation/comparison of editing efficiencies.
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