Morpholino oligonucleotides useful in cancer treatment
Inventors
Ambady, Prakash • Wu, Jeffrey • Neuwelt, Edward
Assignees
Oregon Health and Science University • US Department of Veterans Affairs
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Publication Number
US-11679121-B2
Publication Date
2023-06-20
Expiration Date
2039-07-25
Abstract
Disclosed are morpholino oligonucleotides that can be used to silence expression of MGMT, pharmaceutical compositions that include said morpholino oligonucleotides, and methods of using said morpholino oligonucleotides in the treatment of cancer, particularly methods that involve the use of radiation to deliver said morpholino oligonucleotides.
Core Innovation
The invention relates to morpholino oligonucleotides that can silence expression of the enzyme O-6-methylguanine-DNA methyltransferase (MGMT). These morpholino oligonucleotides, their pharmaceutical compositions, and methods of use are disclosed, particularly involving the use of radiation to enhance delivery of the morpholino oligonucleotides in the treatment of cancer.
MGMT plays a major role in resistance of tumors such as glioblastoma to chemoradiotherapy (CRT) by repairing DNA damage caused by radiation and alkylating agents like temozolomide. Approximately 45% of glioblastomas have epigenetic silencing of MGMT, enhancing tumor susceptibility to CRT. Existing strategies to inhibit MGMT, including pseudo-substrates and small interfering RNA, have limited clinical success due to toxicity and delivery challenges.
The invention addresses this problem by providing morpholino oligonucleotides targeting MGMT with improved delivery methods. It was found that ionizing radiation enhances intracellular delivery of morpholino antisense oligonucleotides, enabling efficient MGMT knockdown both in vitro and in vivo. The morpholino oligonucleotides are designed with specific sequences of no more than 40 subunits, including SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, alone or in combination.
Claims Coverage
The patent includes six independent claims covering methods of treating tumors, enhancing delivery of morpholino oligonucleotides, and compositions comprising specific oligonucleotide sequences.
Method of treating tumors overexpressing MGMT with morpholino oligonucleotides
Administering a composition comprising a morpholino oligonucleotide comprising SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3, where the oligonucleotide is no more than 40 subunits in length, to treat tumors that overexpress MGMT.
Method of treating tumors with morpholino oligonucleotides combined with ionizing radiation
Administering a dose of ionizing radiation to the tumor, with doses of at least 1 Gy or 5 Gy, where the radiation is administered prior to the oligonucleotide composition and at least 24 hours before administration.
Method of enhancing delivery of morpholino oligonucleotides by radiation
Administering a therapeutically effective amount of radiation prior to administering morpholino oligonucleotides comprising SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3, with the oligonucleotides being no more than 40 subunits in length, to a subject with cancer.
Use of specific morpholino oligonucleotide sequences in treatment
Using morpholino oligonucleotides that consist of or comprise SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3 in various combinations but excluding others, for treatment or delivery enhancement purposes.
Method involving determination of MGMT overexpression prior to treatment
Determining that a tumor overexpresses MGMT by measuring MGMT protein expression or resistance to temozolomide before administering the morpholino oligonucleotide composition.
Method of administration
Administering the morpholino oligonucleotide composition intravenously to treat tumors, including malignant tumors located in the lungs or brain, such as glioma or non-small cell lung cancer.
The independent claims broadly cover methods for treating MGMT-overexpressing tumors by administering specific morpholino oligonucleotides alone or combined with radiation and/or temozolomide, methods of enhancing oligonucleotide delivery via radiation, and compositions comprising defined oligonucleotide sequences.
Stated Advantages
Ionizing radiation enhances intracellular delivery of morpholino oligonucleotides to tumor cells, increasing efficacy of MGMT protein knockdown.
Combination of morpholino oligonucleotides with radiation and temozolomide enhances cytotoxic effects in resistant tumor cell lines.
Use of morpholino oligonucleotides allows specific inhibition of MGMT with potential for reduced toxicity compared to other inhibitors.
The morpholino oligonucleotides are resistant to nucleases, have high specificity and safety profiles, and can be delivered systemically with enhanced tumor uptake.
Documented Applications
Treatment of tumors characterized by overexpression of MGMT, including glioblastoma, lung cancer, non-small cell lung cancer, and other solid tumors.
Methods to enhance delivery of morpholino oligonucleotides to tumors by administering ionizing radiation prior to oligonucleotide treatment.
Combination therapies comprising morpholino oligonucleotides, ionizing radiation, and chemotherapeutic agent temozolomide to treat MGMT-overexpressing tumors.
Use of morpholino oligonucleotides to induce apoptosis in cancer cells overexpressing MGMT in vitro and in vivo.
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