Method of promoting survival and/or function of a motor neuron and related agents, uses and methods
View Patent ↗There is provided a method of promoting survival and/or function of an amyotrophic lateral sclerosis (ALS) or ALS-like motor, the method comprising contacting the motor neuron with an agent capable of reducing mitochondrial protein acetylation, particularly an agent selected from a deacetylase activator, such as nicotinamide (NAM) and 7-hydroxy-3-(4′-methoxyphenyl) coumarin (C12), or an acetyltransferase inhibitor, such as GCN5L1 siRNA of SEQ ID NO: 1. Also provided are related agents, oligonucleotides, uses and methods of identifying agents.
1 . A method of promoting survival and/or function of an amyotrophic lateral sclerosis (ALS) motor neuron, the method comprising contacting the motor neuron with an agent capable of reducing mitochondrial protein acetylation, wherein the agent is an acetyltransferase inhibitor comprising a GCN5L1 (GCN5 (general control of amino acid synthesis 5)-like 1) inhibitor comprising an oligonucleotide that is selected from an oligonucleotide comprising complementary to a CDS of BLOC1S1 gene, or SEQ ID NO: 3, or SEQ ID NO: 4; or a sequence sharing at least 95% sequence identity thereof, or an oligonucleotide comprising a sequence sharing at least 95% sequence identity with SEQ ID NO: 1, or a sequence differing from SEQ ID NO: 1 by no more than, 1, 2, 3, 4, or 5 nucleotides.
2 . The method of claim 1 , wherein the GCN5L1 inhibitor comprises an oligonucleotide selected from the group consisting of: antisense oligonucleotide (ASO), gapmer, short interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), single guide RNA (sgRNA) and combinations thereof.
3 . The method of claim 1 , wherein GCN5L1 inhibitor comprises an oligonucleotide comprising:
a) a sequence that is complementary to a coding sequence (CDS) of BLOC1S1 gene, or SEQ ID NO: 3, or SEQ ID NO: 4; or
b) a sequence sharing at least 95% sequence identity with the sequence in a).
4 . The method of claim 1 , wherein the GCN5L1 inhibitor comprises an oligonucleotide comprising a sequence sharing at least 95% sequence identity with SEQ ID NO: 1, or a sequence differing from SEQ ID NO: 1 by no more than, 1, 2, 3, 4, or 5 nucleotides.
5 . The method of claim 1 , wherein, the method further comprising treating ALS in a subject in need thereof, wherein said treatment comprises administering the agent capable of reducing mitochondrial protein acetylation into the subject.
6 . The method of claim 2 , wherein the oligonucleotide comprises a sequence sharing at least 95% sequence identity with SEQ ID NO: 1, or a sequence differing from SEQ ID NO: 1 by no more than, 1, 2, 3, 4, or 5 nucleotides.
7 . The method of claim 3 , wherein the oligonucleotide comprises a sequence sharing at least 95% sequence identity with SEQ ID NO: 1, or a sequence differing from SEQ ID NO: 1 by no more than, 1, 2, 3, 4, or 5 nucleotides.
8 . The method of claim 1 , wherein the oligonucleotide comprises SEQ ID NO: 1, or a sequence differing from SEQ ID NO: 1 by no more than, 1, 2, 3, 4, or 5 nucleotides.