Methods for treating cancer using nucleic acids targeting MDM2 or MYCN
Inventors
Byrne, Michael • Bulock, Karen G. • Cardia, James
Assignees
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Publication Number
US-11279934-B2
Publication Date
2022-03-22
Expiration Date
Abstract
Aspects of the invention relate to methods for treating cancer by administering to a subject in need thereof a therapeutically effective amount of a nucleic acid molecule that is directed against a gene encoding mouse double minute 1 homolog (MDM1), mouse double minute 2 homolog (MDM2), mouse double minute 3 homolog (MDM3), mouse double minute 4 homolog (MDM4) or V-myc myelocytomatosis viral related oncogene (MYCN) for treating cancer. Further aspects of the invention relate to nucleic acid molecules and compositions comprising nucleic acid molecules.
Core Innovation
The invention relates to treating cancer by administering to a subject a therapeutically effective amount of an isolated double stranded nucleic acid molecule directed against a gene encoding mouse double minute 2 homolog (MDM2). The nucleic acid molecule comprises a sense strand and an antisense strand, and the sense strand comprises SEQ ID NO: 727 while the antisense strand comprises SEQ ID NO: 752.
The disclosure describes chemically modified self-delivering asymmetric double-stranded RNAi molecules (sd-rxRNAs) directed against MDM1/MDM2/MDM3/MDM4 or MYCN, with RNAi/RISC/miRNA-like inhibition. The guide and passenger strands of the double stranded region and single stranded regions participate in gene silencing, and chemical modification patterns and stability considerations are emphasized to support functional activity and minimize undesired effects.
The disclosure further describes ocular delivery for cancer treatment, including topical/eye delivery and intravitreal, subretinal, and subconjunctival administration. It also describes sd-rxRNA structure requirements, including a minimal duplex region length and guide single-stranded region length, along with backbone/nucleotide modification percentages and thermodynamic stability considerations using ΔG thresholds.
Claims Coverage
The claim coverage includes one independent claim directed to treating cancer with an isolated double stranded nucleic acid molecule directed against MDM2, comprising a sense strand and an antisense strand. The independent claim is defined by 2 inventive features, with dependent claims further limiting cancer type, ocular location, administration routes, additional nucleic acid regimen, and administration frequency.
Treating cancer with an isolated double stranded MDM2-directed nucleic acid molecule
A method for treating cancer by administering to a subject a therapeutically effective amount of an isolated double stranded nucleic acid molecule directed against a gene encoding mouse double minute 2 homolog (MDM2), wherein the nucleic acid molecule comprises a sense strand and an antisense strand.
Using specified sense and antisense strand sequences for the MDM2-directed nucleic acid molecule
The sense strand comprises SEQ ID NO: 727 and the antisense strand comprises SEQ ID NO: 752.
Cancer selected from retinoblastoma, neuroblastoma, or glioblastoma
The method further applies the treatment to cancer selected from retinoblastoma, neuroblastoma, or glioblastoma.
Cancer located in the retina
The method further specifies that the cancer is located in the retina.
Ocular composition and administration routes
The method further includes formulating the isolated double stranded nucleic acid molecule in a composition for intravitreal injection, subretinal injection, or subconjunctival administration.
Second double stranded nucleic acid regimen
The method further includes administering a second isolated double stranded nucleic acid molecule that targets a gene encoding a different protein or the same protein.
More than once administration
The method is further specified by administering the isolated double-stranded nucleic acid molecule more than once.
Overall, the claim coverage is grounded in administering a therapeutically effective amount of an isolated double stranded nucleic acid molecule with an MDM2-directed sense/antisense design, with dependent limitations to particular cancer types and ocular settings, specified ocular administration routes, an optional second double stranded nucleic acid, and administration more than once.
Stated Advantages
Provides MDM2 silencing localized to tumor cells following intravitreal delivery in retinoblastoma models.
Maintains MDM2 silencing for at least 6 days after a single administration.
Aims to achieve serum stability.
Aims to avoid off-target gene silencing.
Aims to avoid or reduce an interferon response.
Documented Applications
Treating cancer by administering an MDM2-directed isolated double stranded nucleic acid molecule to a subject.
Applying the treatment to cancer selected from retinoblastoma, neuroblastoma, or glioblastoma.
Treatment of cancer located in the retina.
Ocular delivery for cancer treatment, including topical/eye delivery and intravitreal, subretinal, or subconjunctival administration.
Treatment of retinoblastoma using intravitreal delivery enabling MDM2 silencing lasting at least 6 days after a single administration.
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