Microrna dosing regimens

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A method of treating a subject, for example for a subject with a solid tumor or hematologic malignancy, can include administering a therapeutic treatment cycle to the subject, the cycle including daily microRNA mimic administrations on the first 3-7 consecutive days of the cycle followed by no microRNA administration on the next 7-21 consecutive days of the cycle.
Micro-ribonucleic acids (microRNAs) belong to a class of small non-coding RNAs. They regulate many biological processes, including the cell cycle, cell growth and differentiation, stress response and apoptosis. Alterations in microRNA synthesis occur in human cancers and these are often linked to tumor development, progression and metastasis. Epigenetic alterations and mutations of microRNA expression may promote tumor formation as well as increased tumor aggressiveness, invasion, metastasis and resistance to chemotherapy and radiotherapy. It has been postulated that deregulation of microRNA synthesis, which regulates protein synthesis, is one of the most important factors implicated in cancer development.
These findings suggest novel ways of blocking cancer-related cell proliferation, by re-expression of microRNAs inhibited or silenced by cancer development or by inhibiting oncogenic microRNAs. This might be achieved by introducing molecules that mimic the expression of protective microRNAs that are down-regulated in cancer, or by introducing synthetic antisense molecules complementary to the microRNA of interest and which inhibit oncogenic microRNAs overexpressed in cancer cells (i.e. antagomiRs, anti- miRs).
One of the best-characterized microRNAs to date is microRNA-34 (miR-34).
Human miR-34 comprises three family members: miR-34a, miR-34b and miR-34c. These miR-34 genes are frequently inactivated or expressed at reduced levels in numerous cancer types. miR-34a-c frequently functions downstream of p53 by regulating genes that induce cell cycle arrest, cellular senescence and apoptosis.
The re-introduction of miR-34a inhibits cancer cell growth both in vitro and in vivo. Therapeutic activity of miR-34a has been demonstrated in animal models of non-small cell lung cancer, prostate cancer, melanoma, pancreatic cancer and lymphoma, generally showing 50% to 83% tumor growth inhibition. In order to efficiently deliver miR-34a to tumors in vivo upon intravenous administration, Mirna Therapeutics has evaluated multiple existing delivery systems that are in pre-clinical development or have already entered clinical testing with other oligonucleotide therapeutics. Based on this systemic evaluation program, Mirna Therapeutics has selected a liposomal delivery formulation which is complexed with synthetically produced mimics of miR-34a, and which constitutes the therapeutic drug candidate, MRX34. Evaluations of efficacy in murine cancer models, microRNA bio- distribution and preliminary safety have been performed.
Nucleic acid delivery technologies are being developed in connection with various nucleic acids therapeutic candidates. One delivery technology is liposomes, for example amphoteric liposomes like Marina Biotech's SMARTICLES. Amphoteric liposomes are a class of liposomes, which are pH dependent charge-transitioning particles that can provide for the delivery of a nucleic acid payload (e.g., siRNA, microRNA, antisense, etc.) to cells either by local or systemic administration. Amphoteric liposomes can be designed to release their nucleic acid payload within the target cell where the nucleic acid can then engage a number of biological pathways, and thereby exert a therapeutic effect.
ProNAi Therapeutics has used the NOV340 SMARTICLES® liposomal formulation encapsulating a single-stranded DNA that targets BCL2. With ProNAi' s formulation 2 complete remission and 1 partial remission were observed out of 6 patients with either follicular lymphoma or diffuse large B-cell lymphoma. Out of 9 patients with evaluable safety information, the following drug-related adverse events were seen: nausea (8 pts); chills (6 pts); diarrhea (5 pts); fever, tumor pain, vomiting (5 pts each); and anorexia, back pain, fatigue (3 pts each). Most of these adverse events were of low grade and no grade 4 toxicity was observed.
ProNAi Therapeutics has completed a phase I study (ClinicalTrials.gov
Identifier: NCT01191775) in Patients With Advanced Solid Tumors, and has an ongoing phase II study (ClinicalTrials.gov Identifier: NCT01733238) for Treatment of Relapsed or Refractory Non-Hodgkin's Lymphoma, both using a liposome encapsulated oligonucleotide (DNA Interference, or DNAi) drug substance that was administered by intravenous infusion once daily for 5 consecutive days of a 21 -day cycle.
Tekmira Pharmaceuticals has used lipid nanoparticles which share some similarity with NOV340 SMARTICLES® to deliver oligonucleotides directed against PLK and found tumor responses in patients with adrenocortical carcinoma and neuroendocrine tumor. [0010] As of March 2013, Mirna Therapeutics (Austin, TX) has completed the preclinical development program to support the manufacture of cGMP-materials and the conduction of IND-enabling studies for a miR-34-based supplementation therapy (MRX34). Mirna Therapeutics evaluated the toxicity as well as the pharmacokinetic profile of the formulation containing miR-34 mimic in non-GLP pilot studies using mice, rats and non- human primates. These experiments did not show adverse events at the predicted therapeutic levels of MRX34, as measured by clinical observations, body weights, clinical chemistries (including LFT, RFT and others), hematology, gross pathology, histopathology of select organs and complement (CH50). In addition, miRNA mimics formulated in lipid nanoparticles do not induce the innate immune system as demonstrated in fully immunocompetent mice, rats, non-human primates, as well as human whole blood specimens. A more detailed review of the pre-clinical data is provided in Bader, Front Genet. 2012; 3: 120. Clinical trials are ongoing and, as of March 27, 2014, twenty-nine patients have been treated with MRX34, three at 10 mg/m 2, six at 20 mg/m 2, three at 33 mg/m 2, eight at 50 mg/m 2, seven at 70 mg/m 2, and two at 93 mg/m on a twice weekly dosing schedule.

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