STAUFEN1 regulating agents and associated methods
Methods of minimizing dysregulation of Staufen1-associated RNA metabolism can include introducing an amount of a Staufen1-regulating agent to a target cell sufficient to minimize the dysregulation. Therapeutic compositions for treating a neurodegenerative condition associated with Staufen1-induced dysregulation of RNA metabolism can include a therapeutically effective amount of a Staufen1-regulating agent and a pharmaceutically acceptable carrier.
1 . A method of treating a neurological condition associated with a mutation of the C9orf72 gene, the TDP-43 gene, the HTT gene, the PSEN1 gene, the MAPT gene, or a combination thereof, comprising:
introducing an amount of a Staufen1-regulating agent to a target cell that is sufficient to minimize Staufen1-induced dysregulation of RNA metabolism,
wherein the Staufen1-regulating agent comprises a nucleotide sequence that is at least 80% homologous to the 10 middle nucleotides of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, or a combination thereof; or
wherein the Staufen1-regulating agent comprises a nucleotide sequence includes the 10 middle nucleotides of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, or a combination thereof; or
wherein the Staufen1-regulating agent comprises a nucleotide sequence that is at least 80% homologous to and having the same number of nucleotides as SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, or a combination thereof.
2 . The method of claim 1 , wherein introducing comprises introducing the Staufen1-regulating agent to the target cell with a non-viral vector.
3 . The method of claim 2 , wherein the non-viral vector is a non-viral carrier selected from the group consisting of: an aptamer, an antibodies, an antibody fragment, a polypeptides, N-acetylgalactosamine, a vitamin, a small organic molecules, a polycationic peptide, a polymers, a dendrimer, a lipid, a lysosomal carrier, a liposome, a micelle, a quantum dot, a nanoparticle, and combinations thereof.
4 . The method of claim 1 , wherein introducing comprises introducing the Staufen1-regulating agent to the target cell with a viral vector.
5 . The method of claim 3 , wherein the viral vector is a member of the group consisting of: a retrovirus, a lentivirus, a cytomegalovirus, an adenovirus, an adeno-associated virus, and combinations thereof.
6 . The method of claim 1 , wherein introducing comprises introducing the Staufen1-regulating agent without a delivery vector.
7 . The method of claim 1 , wherein the amount of Staufen 1-regulating agent increases PCP2 mRNA levels in the target cell, CALB1 mRNA levels in the target cell, or both as compared to said levels prior to or without introducing the Staufen1-regulating agent.
8 . The method of claim 1 , wherein the amount of Staufen 1-regulating agent reduces Staufen1 levels in the target cell by at least 30% as compared to Staufen1 levels in the target cell prior to or without introduction of the Staufen1-regulating agent.
9 . The method of claim 1 , wherein the Staufen1-regulating agent reduces Staufen1 expression, reduces Staufen1 activity, reduces or blocks Staufen1 interaction with mRNAs resulting in altered mRNA expression or abundance, or a combination thereof.
10 . The method of claim 1 , wherein Staufen1-regulating agent is administered as part of a composition including a pharmaceutically acceptable carrier.
11 . The method of claim 10 , wherein the pharmaceutically acceptable carrier is formulated for administration via injection, enteral administration, transdermal administration, transmucosal administration, inhalation, or implantation.
12 . The method of claim 10 , wherein the pharmaceutically acceptable carrier comprises water, a solubilizing agent, a tonicity agent, a pH adjuster, a buffering agent, a preservative, a chelating agent, a bulking agent, a binder, a disintegrant, a filler, a thickener, a dispersant, an emulsifier, an emollient, or combinations thereof.
13 . The method of claim 10 , wherein the Staufen1-regulating agent is present the composition at a concentration of from about 1 picomolar (pM) to about 100 millimolar (mM).
14 . The method of claim 10 , wherein the Staufen1-regulating agent is present in the composition at a concentration of from about 0.001 μg/g to about 200 mg/g.
15 . The method of claim 1 , further comprising administering a supplementary therapeutic agent.
16 . The method of claim 15 , wherein the supplementary therapeutic agent is a member selected from the group consisting of: a dopaminergic agent, a cholinesterase inhibitor, an antipsychotic agent, an analgesic, an anti-inflammatory agent, an inducer of autophagy, and combinations thereof.