Methods for treating neurodegenerative diseases

Abstract

Methods for treating, and for identifying novel treatments for, neurodegenerative diseases, as well as animal and cellular models. The present disclosure shows that age dependent accumulation of genomic lesions leads to the production of RNA molecules within neurons that mimic viruses and intrinsically activate innate immune signaling, which triggers neurodegeneration. This hypothesis is supported by the results shown herein elucidating the mechanism of neurodegeneration in two mouse lines that specifically express different isoforms of the human amyloid precursor protein (hAPP) gene, which is associated with Alzheimer's disease (AD), exclusively in olfactory sensory neurons (OSNs) in the nose.

1 . A method of treating a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of one or more of:
 a small molecule inhibitor of a human interferon alpha 16 (IFNA16), toll-like receptor 3 (TLR3), eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2, aka PKR), interferon induced with helicase C domain 1 (IFIH1, aka MDA5), mitochondrial antiviral signaling protein (MAVS), signal transducer and activator of transcription 1, 91kDa (STAT1), 2′-5′-oligoadenylate synthetase-like (OASL), interferon-induced protein 44 (Ifi44), DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 (DDX58), ribonuclease L (2′,5′-oligoisoadenylate synthetase-dependent) (RNaseL), mitogen-activated protein kinase 14 (MAPK14, aka p38), mitogen-activated protein kinase-activated protein kinase 2 (MapKapK-2), or mitogen-activated protein kinase-activated protein kinase 3 (MapKapK-3) protein;   an inhibitory nucleic acid that targets a IFNA16, TLR3, EIF2AK2, aka PKR, IFIH1, aka MDA5, MAVS, STAT1, OASL, Ifi44, DDX58, RNaseL, MAPK14, aka p38, MapKapK-2, or MapKapK-3 transcript; and/or   an antibody that binds to and inhibits a a IFNA16, TLR3, EIF2AK2, aka PKR, IFIH1, aka MDAS, MAVS, STAT1, OASL, Ifi44, DDX58, RNaseL, MAPK14, aka p38, MapKapK-2, or MapKapK-3 protein;   thereby treating the neurodegenerative disease in the subject.   
     
     
         2 . The method of  claim 1 , wherein the neurodegenerative disease is Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Cockayne Syndrome (CS), Xeroderma Pigmentosum (XP), Trichothiodystrophy (TTD), Ataxia with Occulomotor Apraxia-1 (AOA1), Spinocerebellar Ataxia with Axonal Neuropathy (SCAN1), Ataxia Telangiectasia (A-T) or A-T Like Disease (ATLD), ATR-Seckel Syndrome, Nijmegen Breakage Syndrome (NB S), LIG4 Syndrome, Aicardi-Goutier's syndrome and related interferonopathies, or XLF Syndrome. 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . A method of identifying a candidate compound for treating a neurodegenerative disease, the method comprising contacting a cell, preferably a neuron, wherein the neuron expresses one or more of: (i) an antisense transcript that is at least 35 nt long and is complementary to a sense transcript that is expressed in the cell, and/or (ii) a transgene that results in overexpression of MDA5, activated PKR, or MAVS, wherein expression of the antisense or transgene in the absence of a test compound results in cell death, in the cell, and the cell death occurs via induction of Type 1 interferon signaling;
 contacting the cell with a test compound;   measuring cell death in the presence of the test compound, and   selecting a test compound that reduces or delays cell death as a candidate compound for treating a neurodegenerative disease.   
     
     
         6 . The method of  claim 5 , wherein the antisense transcript, MDA5 transgene, or MAVS transgene is under the control of an inducible promoter and the method includes inducing expression of the antisense transgene in the cell. 
     
     
         7 . The method of  claim 5 , wherein the antisense is complementary to an endogenous sense transcript or to a sense transcript that is expressed from an exogenous coding sequence. 
     
     
         8 . The method of  claim 5 , wherein the cell is in a three-dimensional culture system. 
     
     
         9 . The method of  claim 1 , further comprising:
 expressing in an animal model one or more of: (i) an antisense transcript that is at least 35 nt long and is complementary to a sense transcript that is expressed in the cell, or (ii) a transgene that results in overexpression of MDA5, activated PKR, or MAVS in the olfactory sensory neurons (OSNs) of the animal,   administering a test compound to the animal, and   evaluating cell death, in the animal, and   selecting a test compound that reduces or delays cell death as a candidate compound for treating a neurodegenerative disease.   
     
     
         10 . The method of  claim 12 , wherein the antisense transcript leads to production of a dsRNA molecule in the olfactory sensory neurons (OSNs) of the animal. 
     
     
         11 . The method of  claim 9 , comprising evaluating cell death in the OSNs of the animal. 
     
     
         12 . The method of  claim 9 , comprising evaluating cell death in the neurons in the brain of the animal where the neurodegenerative cascade was initiated in neurons in the nose (OSNs). 
     
     
         13 . The method of  claim 9 , wherein the neurodegenerative disease is Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Cockayne Syndrome (CS), Xeroderma Pigmentosum (XP), Trichothiodystrophy (TTD), Ataxia with Occulomotor Apraxia-1 (AOA1), Spinocerebellar Ataxia with Axonal Neuropathy (SCAN1), Ataxia Telangiectasia (A-T) or A-T Like Disease (ATLD), ATR-Seckel Syndrome, Nijmegen Breakage Syndrome (NBS), LIG4 Syndrome, Aicardi-Goutier's syndrome and related interferonopathies, or XLF Syndrome. 
     
     
         14 . The method of  claim 2 , or the composition for the use of  claim 4 , wherein the amyotrophic lateral sclerosis (ALS) is C9orf72-linked ALS, fused in sarcoma (FUS)-linked ALS, TAR DNA-binding protein 43 (TDP-43)-linked ALS, C9orf72-linked frontotemporal dementia (FTD), FUS-linked FTD, and TDP-43-linked FTD, C9orf72-linked AD, or sporadic ALS. 
     
     
         15 . A transgenic mouse, which has incorporated into its genome one of (a) a transgene driven by TRE that expresses a pathogenic Swedish allele of human APP with amino acid substitution at positions 670 and 671 (K670N, M671L) coupled to an internal ribosome entry sequence (IRES) and a fluorescent marker; (b) a transgene driven by TRE that expresses a synthetic allele of hAPP with an M to V amino acid substitution at position 671 (M671V) followed by an internal ribosome entry sequence (IRES) and a fluorescent marker; or (c) a transgene driven by TRE that expresses a wild type allele of human APP followed by an internal ribosome entry sequence (IRES) and a fluorescent marker, with an additional insertion of an inversion of part of the transgene. 
     
     
         16 . The transgenic mouse of  claim 15 , wherein the , fluorescent marker is GFP or mCherry. 
     
     
         17 . (canceled)