U1 Adaptor Oligonucleotides Targeting BCL2 and GRM1 Suppress Growth of Human Melanoma Xenografts In Vivo
U1 Adaptor is a recently discovered oligonucleotide-based gene-silencing technology with a unique mechanism of action that targets nuclear pre-mRNA processing. U1 Adaptors have two distinct functional domains, both of which must be present on the same oligonucleotide to exert their gene-silencing fu...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2013-01-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253116301548 |
| _version_ | 1811284039665975296 |
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| author | Rafal Goraczniak Brian A Wall Mark A Behlke Kim A Lennox Eric S Ho Nikolas H Zaphiros Christopher Jakubowski Neil R Patel Steven Zhao Carlo Magaway Stacey A Subbie Lumeng Jenny Yu Stephanie LaCava Kenneth R Reuhl Suzie Chen Samuel I Gunderson |
| author_facet | Rafal Goraczniak Brian A Wall Mark A Behlke Kim A Lennox Eric S Ho Nikolas H Zaphiros Christopher Jakubowski Neil R Patel Steven Zhao Carlo Magaway Stacey A Subbie Lumeng Jenny Yu Stephanie LaCava Kenneth R Reuhl Suzie Chen Samuel I Gunderson |
| author_sort | Rafal Goraczniak |
| collection | DOAJ |
| description | U1 Adaptor is a recently discovered oligonucleotide-based gene-silencing technology with a unique mechanism of action that targets nuclear pre-mRNA processing. U1 Adaptors have two distinct functional domains, both of which must be present on the same oligonucleotide to exert their gene-silencing function. Here, we present the first in vivo use of U1 Adaptors by targeting two different human genes implicated in melanomagenesis, B-cell lymphoma 2 (BCL2) and metabotropic glutamate receptor 1 (GRM1), in a human melanoma cell xenograft mouse model system. Using a newly developed dendrimer delivery system, anti-BCL2 U1 Adaptors were very potent and suppressed tumor growth at doses as low as 34 µg/kg with twice weekly intravenous (iv) administration. Anti-GRM1 U1 Adaptors suppressed tumor xenograft growth with similar potency. Mechanism of action was demonstrated by showing target gene suppression in tumors and by observing that negative control U1 Adaptors with just one functional domain show no tumor suppression activity. The anti-BCL2 and anti-GRM1 treatments were equally effective against cell lines harboring either wild-type or a mutant V600E B-RAF allele, the most common mutation in melanoma. Treatment of normal immune-competent mice (C57BL6) indicated no organ toxicity or immune stimulation. These proof-of-concept studies represent an in-depth (over 800 mice in ~108 treatment groups) validation that U1 Adaptors are a highly potent gene-silencing therapeutic and open the way for their further development to treat other human diseases. |
| first_indexed | 2024-04-13T02:22:39Z |
| format | Article |
| id | doaj.art-05875fbc03754cd9bb797287478d6134 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-04-13T02:22:39Z |
| publishDate | 2013-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-05875fbc03754cd9bb797287478d61342022-12-22T03:06:54ZengElsevierMolecular Therapy: Nucleic Acids2162-25312013-01-012C10.1038/mtna.2013.24U1 Adaptor Oligonucleotides Targeting BCL2 and GRM1 Suppress Growth of Human Melanoma Xenografts In VivoRafal Goraczniak0Brian A Wall1Mark A Behlke2Kim A Lennox3Eric S Ho4Nikolas H Zaphiros5Christopher Jakubowski6Neil R Patel7Steven Zhao8Carlo Magaway9Stacey A Subbie10Lumeng Jenny Yu11Stephanie LaCava12Kenneth R Reuhl13Suzie Chen14Samuel I Gunderson15Silagene Inc., Hillsborough, New Jersey, USADepartment of Chemical Biology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, New Jersey, USAIntegrated DNA Technologies Inc., Coralville, Iowa, USAIntegrated DNA Technologies Inc., Coralville, Iowa, USADepartment of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, USADepartment of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, USADepartment of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, USADepartment of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, USADepartment of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, USADepartment of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, USADepartment of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, USADepartment of Chemical Biology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, New Jersey, USADepartment of Chemical Biology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, New Jersey, USADepartment of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, New Jersey, USADepartment of Chemical Biology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, New Jersey, USADepartment of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, USAU1 Adaptor is a recently discovered oligonucleotide-based gene-silencing technology with a unique mechanism of action that targets nuclear pre-mRNA processing. U1 Adaptors have two distinct functional domains, both of which must be present on the same oligonucleotide to exert their gene-silencing function. Here, we present the first in vivo use of U1 Adaptors by targeting two different human genes implicated in melanomagenesis, B-cell lymphoma 2 (BCL2) and metabotropic glutamate receptor 1 (GRM1), in a human melanoma cell xenograft mouse model system. Using a newly developed dendrimer delivery system, anti-BCL2 U1 Adaptors were very potent and suppressed tumor growth at doses as low as 34 µg/kg with twice weekly intravenous (iv) administration. Anti-GRM1 U1 Adaptors suppressed tumor xenograft growth with similar potency. Mechanism of action was demonstrated by showing target gene suppression in tumors and by observing that negative control U1 Adaptors with just one functional domain show no tumor suppression activity. The anti-BCL2 and anti-GRM1 treatments were equally effective against cell lines harboring either wild-type or a mutant V600E B-RAF allele, the most common mutation in melanoma. Treatment of normal immune-competent mice (C57BL6) indicated no organ toxicity or immune stimulation. These proof-of-concept studies represent an in-depth (over 800 mice in ~108 treatment groups) validation that U1 Adaptors are a highly potent gene-silencing therapeutic and open the way for their further development to treat other human diseases.http://www.sciencedirect.com/science/article/pii/S2162253116301548cancer therapydendrimergene silencingoligonucleotide therapeutictumor targeting |
| spellingShingle | Rafal Goraczniak Brian A Wall Mark A Behlke Kim A Lennox Eric S Ho Nikolas H Zaphiros Christopher Jakubowski Neil R Patel Steven Zhao Carlo Magaway Stacey A Subbie Lumeng Jenny Yu Stephanie LaCava Kenneth R Reuhl Suzie Chen Samuel I Gunderson U1 Adaptor Oligonucleotides Targeting BCL2 and GRM1 Suppress Growth of Human Melanoma Xenografts In Vivo Molecular Therapy: Nucleic Acids cancer therapy dendrimer gene silencing oligonucleotide therapeutic tumor targeting |
| title | U1 Adaptor Oligonucleotides Targeting BCL2 and GRM1 Suppress Growth of Human Melanoma Xenografts In Vivo |
| title_full | U1 Adaptor Oligonucleotides Targeting BCL2 and GRM1 Suppress Growth of Human Melanoma Xenografts In Vivo |
| title_fullStr | U1 Adaptor Oligonucleotides Targeting BCL2 and GRM1 Suppress Growth of Human Melanoma Xenografts In Vivo |
| title_full_unstemmed | U1 Adaptor Oligonucleotides Targeting BCL2 and GRM1 Suppress Growth of Human Melanoma Xenografts In Vivo |
| title_short | U1 Adaptor Oligonucleotides Targeting BCL2 and GRM1 Suppress Growth of Human Melanoma Xenografts In Vivo |
| title_sort | u1 adaptor oligonucleotides targeting bcl2 and grm1 suppress growth of human melanoma xenografts in vivo |
| topic | cancer therapy dendrimer gene silencing oligonucleotide therapeutic tumor targeting |
| url | http://www.sciencedirect.com/science/article/pii/S2162253116301548 |
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