Gene editing to improve joint function
Inventors
Millett, Peter J. • Russell, Iain Alasdair • Allen, Matthew J.
Assignees
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Publication Number
US-11324838-B2
Publication Date
2022-05-10
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 disclosed invention relates to a method of treating arthritis in a subject in need thereof by administering to a joint a pharmaceutical composition comprising a recombinant virus. The recombinant virus comprises one or more nucleic acids encoding a CRISPR gene-editing system, and the CRISPR gene-editing system comprises a Cas9 protein and at least one guide RNA.
The guide RNA targets a gene selected from IL-1α, IL-1β, or a combination thereof, and the guide RNA comprises a crRNA sequence that is complementary to a target sequence in exon 4 of the IL-1α or IL-1β gene. The target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein.
The disclosed approach further encompasses delivery of the CRISPR gene-editing system using recombinant viral vectors, including retrovirus, adenovirus, adeno-associated virus, lentivirus, and herpes simplex virus-1. The delivery is described in the context of treating inflammatory joint disorders by editing relevant synovial cells and other joint-associated cells.
Claims Coverage
The content provides one independent claim centered on delivering a CRISPR/Cas9 gene-editing system via a recombinant virus to a joint to target IL-1α and/or IL-1β exon 4 using a guide RNA complementary to a sequence adjacent to a Cas9 PAM. Dependent claims narrow delivery vector options and administration timing and route.
Joint administration of a recombinant CRISPR gene-editing virus for arthritis treatment
A method of treating arthritis in a subject in need thereof, the method comprising administering to a joint a pharmaceutical composition comprising a recombinant virus comprising one or more nucleic acids encoding a CRISPR gene-editing system.
Cas9 and guide RNA targeting IL-1α or IL-1β exon 4 adjacent to a Cas9 PAM
The CRISPR gene-editing system comprises a Cas9 protein and at least one guide RNA targeting a gene selected from IL-1α, IL-1β, or a combination thereof, wherein the at least one guide RNA comprises a crRNA sequence complementary to a target sequence in exon 4 of the IL-1α or IL-1β gene and the target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein.
Recombinant virus selection from multiple viral classes
The recombinant virus is selected from retrovirus, adenovirus, adeno-associated virus, lentivirus, and herpes simplex virus-1.
Intra-articular administration
The method includes administering the pharmaceutical composition by intra-articular injection into the joint of the subject.
Administration during surgery
The method includes administering the pharmaceutical composition during surgery.
CRISPR guide RNA constrained to specified crRNA sequences
The method is limited to using a crRNA sequence selected from SEQ ID NOs: 21-34.
Across the independent claim and listed dependents, the coverage is directed to arthritis treatment by administering a recombinant virus encoding a CRISPR/Cas9 system to a joint. The guide RNA is defined by exon 4 targeting of IL-1α and/or IL-1β with adjacency to a Cas9 PAM. Additional dependent limitations specify particular viral classes for delivery, intra-articular and surgery-related administration, and constrained crRNA sequence options.
Stated Advantages
Documented Applications
Treating arthritis in a subject in need thereof by administering to a joint a recombinant virus delivering a CRISPR gene-editing system targeting IL-1α and/or IL-1β.
Evaluating CRISPR gene-editing outcomes related to IL-1 in joint-related disease contexts described in the document, including IL-1 knockdown using CRISPR AAV in mouse osteoarthritis models and in vitro cleavage/editing efficiency comparisons.
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