Compositions for the treatment of disease

Abstract

The invention provides compositions and methods for the preparation, manufacture and therapeutic use of viral vectors, such as adeno-associated virus (AAV) particles having viral genomes encoding one or more antibodies or antibody fragments or antibody-like polypeptides, for the prevention and/or treatment of diseases and/or disorders.

1 . An adeno-associated virus (AAV) particle comprising a capsid and a viral genome, said viral genome comprising at least one inverted terminal repeat (ITR) region, a first nucleic acid and/or a second nucleic acid, wherein said first nucleic acid and said second nucleic acid independently encode or comprise a nucleotide sequence, or encode an amino acid sequence of, any of Tables 3-12, or a fragment thereof. 
     
     
         2 . The AAV particle of  claim 1 , wherein the capsid comprises an AAV9 capsid protein, an AAV5 capsid protein, an AAV2 capsid protein, or functional variant thereof. 
     
     
         3 . The AAV particle of  claim 1 , wherein the viral genome further comprises a promoter operably linked to the first nucleic acid, the second nucleic acid, or both the first nucleic acid and the second nucleic acid, wherein the promoter comprises a tissue specific promoter or a ubiquitous promoter. 
     
     
         4 . The AAV particle of  claim 3 , wherein the promoter comprises an elongation factor 1α-subunit (EF1α) promoter, a cytomegalovirus (CMV) immediate-early enhancer and/or promoter, a chicken β-actin (CBA) promoter and/or its derivative CAG, a β glucuronidase (GUSB) promoter, or a ubiquitin C (UBC) promoter, a neuron-specific enolase (NSE), a platelet-derived growth factor (PDGF) promoter, a platelet-derived growth factor B-chain (PDGF-β) promoter, an intercellular adhesion molecule 2 (ICAM-2) promoter, a synapsin promoter, a methyl-CpG binding protein 2 (MeCP2) promoter, a Ca2+/calmodulin-dependent protein kinase II (CaMKII) promoter, a metabotropic glutamate receptor 2 (mGluR2) promoter, a neurofilament light (NFL) or heavy (NFH) promoter, a β-globin minigene nβ2 promoter, a preproenkephalin (PPE) promoter, an enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2), a glial fibrillary acidic protein (GFAP) promoter, a myelin basic protein (MBP) promoter, or a functional variant thereof. 
     
     
         5 . The AAV particle of  claim 1 , wherein the viral genome is single stranded or self-complementary. 
     
     
         6 - 7 . (canceled) 
     
     
         8 . The AAV particle of claim  7 , wherein the first nucleic acid is codon-optimized, the second nucleic acid is codon-optimized, or both the first nucleic acid and the second nucleic acid are codon optimized. 
     
     
         9 . The AAV particle of  claim 1 , wherein the viral genome comprises, from 5′ to 3′:
 (i) the first nucleic acid and the second nucleic acid: or, 
 (ii) the second nucleic acid and the first nucleic acid. 
 
     
     
         10 . (canceled) 
     
     
         11 . The AAV particle of  claim 1 , wherein the viral genome further comprises a linker, wherein the linker comprises a T2A peptide, an internal ribosome entry site (IRES), an F2A peptide, a furin cleavage site, a glycine serine linker, or a combination thereof. 
     
     
         12 - 14 . (canceled) 
     
     
         15 . The AAV particle of  claim 1 , wherein the the viral genome further comprises:
 (i) an enhancer;   (ii) an intron;   (iii) a Kozak sequence; and/or   (iv) a polyadenylation sequence.   
     
     
         16 . The AAV particle of  claim 15 , wherein the enhancer comprises a Cytomegalovirus Major Immediate-Early (CMVie) enhancer. 
     
     
         17 . The AAV particle of  claim 15 , wherein the intron comprises a β-globin intron or an SV40 intron. 
     
     
         18 . (canceled) 
     
     
         19 . The AAV particle of  claim 1 , wherein the first nucleic acid encodes a first polypeptide sequence, and the second nucleic acid encodes a second polypeptide sequence, wherein the first and the second polypeptide sequences are expressed as a single polypeptide. 
     
     
         20 . (canceled) 
     
     
         21 . The AAV particle of  claim 1 , wherein the viral genome encodes an antibody, a bispecific antibody, a single-antigen binding domain, a nanobody, a VHH, an scFv, a diabody, an Fab, an Fab′, oran F(ab′) 2 . 
     
     
         22 . (canceled) 
     
     
         23 . A method of delivering an antibody to a subject, comprising administering to said subject the AAV particle of  claim 1 , thereby delivering the antibody to the subject. 
     
     
         24 - 26 . (canceled) 
     
     
         27 . A pharmaceutical composition comprising an AAV particle of  claim 1  in a pharmaceutically acceptable excipient. 
     
     
         28 - 46 . (canceled) 
     
     
         47 . A method of treating a disease or disorder in a subject comprising administering to said subject the AAV article of  claim 1 . 
     
     
         48 . The method of  claim 47 , wherein said disease or disorder is selected from Parkinson's Disease, Dementia with Lewy Bodies, multiple system atrophy, decreased muscle mass, decreased muscle strength, decreased muscle function, spinal muscular atrophy, Alzheimer's Disease, Huntington's Disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke, migraine, pain, neuropathies, psychiatric disorders, cancer, ocular diseases, systemic diseases of the blood, systemic diseases of the heart, systemic diseases of the bone, immune system, autoimmune disease, inflammation disorders or inflammation. 
     
     
         49 - 70 . (canceled) 
     
     
         71 . The AAV particle of  claim 1 , wherein the first nucleic acid encodes a heavy chain variable domain and the second nucleic acid encodes a light chain variable domain. 
     
     
         72 . The AAV particle of  claim 1 , wherein the first nucleic acid and the second nucleic acid each comprise the nucleotide sequence or encodes the amino acid sequence of any one of SEQ ID NOs: 2977-2998, 3031-3039, 3060-3076, 3129-3147, 3181-3196, 3205-3226, 3277-3285, 3335-3345, 3375-3382, 3453-3459, 3856, 3890-3898, 4232-4237, 4308, 4323, 4420, 4431, 4501-4504, 4512-4527, or 4535-17658. 
     
     
         73 . The method of  claim 47 , wherein the AAV particle is administered to the subject intravenously, intratumorally, or via intracisternal injection.