Pharmaceutical composition comprising Nanog shRNA, and method of using Nanog shRNA to treat cancer
Inventors
Jessup, John Milburn • Korokhov, Nikolay
Assignees
US Department of Health and Human Services
Publication Number
US-9988631-B2
Publication Date
2018-06-05
Expiration Date
2031-12-06
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Abstract
The present description relates to an inhibitory RNA molecule, comprising an oligonucleotide that selectively knocks down expression a Nanog pseudogene expressed in many human cancers, a replicating viral vector capable of encoding such inhibitory RNA molecule, pharmaceutical compositions comprising said vector, and methods of treating cancer by administration of said pharmaceutical composition.
Core Innovation
The invention relates to an inhibitory RNA molecule comprising an oligonucleotide that selectively knocks down expression of Nanog or a Nanog pseudogene, including NanogP8, which is expressed in many human cancers such as colorectal carcinoma (CRC). The invention also includes viral vectors, particularly lentivirus vectors and conditionally replicating adenovirus vectors, capable of encoding such inhibitory RNA molecules, pharmaceutical compositions comprising these vectors, and methods of treating cancer by administering these pharmaceutical compositions to patients in need thereof.
The background identifies colorectal carcinoma as one of the most lethal cancers with a high need for effective therapeutics. Nanog, a core embryonic stem cell gene, and its related pseudogenes like NanogP8, are expressed and functionally important in various cancers, including CRC, breast, prostate, glioblastoma, and cervical cancers. Nanog expression is linked to tumor development and cancer stem cell properties, which contribute to tumor heterogeneity and resistance. However, the specific role of Nanog pseudogenes such as NanogP8 in tumorigenesis and metastasis progression is not understood, creating a need for targeted therapies to inhibit their function.
The summary describes allele-specific inhibitory RNA molecules, such as shRNA sequences selected from SEQ ID NOS:3-44, that can selectively knock down Nanog or NanogP8 gene expression without affecting the other. Lentiviral and replicating viral vectors including conditionally replicating oncolytic adenoviruses (CRAd), especially the Ad5/3 fiber modified vectors, are engineered to deliver such RNA molecules selectively to cancer cells. The vectors can infect cancer cells, induce apoptosis, inhibit proliferation, and reduce tumor mass and metastasis, particularly for colorectal cancer. Pharmaceutical compositions comprising these vectors or RNA molecules are provided along with methods for treating cancers by administering an effective amount of these compositions to patients.
Claims Coverage
The patent contains one independent method claim directed to treating colorectal cancer using an inhibitory RNA molecule targeting NanogP8 and various dependent claims covering delivery methods and vector types.
Method of treating colorectal cancer by knocking down NANOGP8 expression
A method comprising administering to a patient a therapeutically effective amount of an inhibitory RNA molecule comprising an oligonucleotide that knocks down expression of NANOGP8, specifically sequences selected from SEQ ID NO:3, SEQ ID NO:8, and SEQ ID NO:56.
Inhibition of metastasizing cancer cells
The method includes inhibiting cancer cells capable of metastasizing as part of treating colorectal cancer.
Administration routes for inhibitory RNA molecule
Administration is via intravenous administration or direct injection at the site of disease.
Use of double stranded siRNA as inhibitory RNA
The inhibitory RNA molecule can be a double stranded siRNA comprising specific sense and antisense sequences selected from SEQ ID NOS:54-57.
Use of conditionally replicating viral vector
The patient is administered a conditionally replicating viral vector comprising the inhibitory RNA molecule.
Use of conditionally replicating adenovirus with 5/3 fiber (CRAd5/3)
The conditionally replicating viral vector is specifically a conditionally replicating adenovirus with a 5/3 fiber, termed CRAd5/3.
The claims cover a method of treating colorectal cancer through administration of allele-specific inhibitory RNA molecules targeting NanogP8, with inventive features relating to specific RNA sequences, inhibition of metastatic cells, administration routes, and the use of conditionally replicating viral vectors including CRAd5/3 adenovirus vectors.
Stated Advantages
Inhibitory RNA molecules and viral vectors specifically knock down Nanog variants linked to cancer without affecting the other Nanog forms.
Targeting NanogP8 inhibits spherogenicity, tumorigenicity, and metastasis of colorectal cancer cells.
Conditionally replicating adenovirus vectors with modified 5/3 fiber reduce hepatotoxicity and enhance tumor-specific replication.
Viral vectors can infect cancer stem cell populations and inhibit tumor growth and metastasis effectively in vitro and in vivo.
Allele-specific inhibition preserves normal Nanog function while targeting cancer-associated Nanog pseudogenes, potentially reducing side effects.
Documented Applications
Treatment of colorectal cancer, including inhibiting cancer cells capable of metastasizing.
Use in treating cancers expressing Nanog or NanogP8, including breast, gastric, glioblastoma, and cervical cancers.
Use of viral vectors such as lentivirus or conditionally replicating adenovirus for delivery of inhibitory RNA molecules to cancer cells.
Administration via intravenous injection or direct intratumoral injection to inhibit tumor growth and metastasis.
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