Intrathecal administration of adeno-associated-viral vectors for gene therapy

Abstract

A composition comprising at least one AAV vector formulated for intrathecal delivery to the central nervous system is described. The composition comprises at least one expression cassette which contains sequences encoding an immunoglobulin construct linked to expression control sequences therefor and a pharmaceutically acceptable carrier. The immunoglobulin construct may be an immunoglobulin modified to have decreased or no measurable affinity for neonatal Fc receptor (FcRn).

1 . A composition formulated for intrathecal delivery comprising at least one recombinant adeno-associated virus (rAAV) for treatment of a neurodegenerative disorder selected from one or more of Parkinson's disease, amyotropic lateral sclerosis (ALS), multiple sclerosis, Alzheimer's Disease, Huntington disease, traumatic brain injury, spinal cord injury, migraine, stroke, and/or an infectious disease, wherein said at least one rAAV comprises an AAV capsid which targets a cell of the central nervous system, the capsid having packaged therein sequences encoding an immunoglobulin construct operably linked to expression control sequences therefor, the composition further comprising a pharmaceutically acceptable carrier and/or excipient. 
     
     
         2 . The composition according to  claim 1 , wherein the immunoglobulin construct is selected from a single chain variable fragment antibody (scFv), an Fv, Fab, F(ab) 2 , F(ab) 3 , Fab′, Fab′-SH, F(ab′) 2 , an immunoadhesin, a monoclonal antibody, a heavy chain camelid or shark immunoglobulins. 
     
     
         3 . The composition according to  claim 1 , wherein the disorder is Alzheimer's Disease and the composition comprises at least one rAAV stock expressing an immunoglobulin specific for a Aβ, beta secretase, and/or tau protein. 
     
     
         4 . The composition according to  claim 3 , wherein the immunoglobulin is a scFv. 
     
     
         5 . The composition according to  claim 4 , wherein the scFv has the amino acid sequence selected from SEQ ID NO: 8, SEQ ID NO: 10 or SEQ ID NO:12. 
     
     
         6 . The composition according to  claim 1 , wherein the composition comprises rAAV stock comprising at least two different antibody expression cassettes. 
     
     
         7 . The composition according to  claim 1 , wherein the composition comprises a AAV stock comprising a single immunoglobulin expression cassette. 
     
     
         8 . The composition according to  claim 1 , wherein the composition is delivered intrathecally and treats the condition both in the central nervous system and systemically. 
     
     
         10 . The composition according to  claim 1 , wherein the immunoglobulin construct comprises an immunoglobulin modified to have decreased or no measurable affinity for neonatal Fc receptor (FcRn). 
     
     
         11 . A composition useful for treatment of Alzheimer's Disease comprising at least one AAV vector stock comprising an AAV capsid which targets a cell of the central nervous system, the capsid having packaged therein at least one AAV inverted terminal repeat sequence and sequences encoding an immunoglobulin construct operably linked to expression control sequences therefor, wherein the at least one vector stock expresses an immunoglobulin specific for a Aβ, beta secretase, and/or the tau protein, and the composition further comprises a pharmaceutically acceptable carrier and/or excipient. 
     
     
         12 . The composition according to  claim 11 , wherein the immunoglobulin is a scFv. 
     
     
         13 . The composition according to  claim 12 , wherein the scFv has the amino acid sequence selected from SEQ ID NO: 8, SEQ ID NO: 10 or SEQ ID NO:12. 
     
     
         14 . A method for treatment of Alzheimer's Disease, said method comprising delivering intrathecally a composition according to  claim 1 , in which the composition comprises at least one vector stock expressing an immunoglobulin specific for a Aβ, beta secretase, and/or the tau protein, to subject in need thereof. 
     
     
         15 . A method for treatment of ALS, said method comprising delivering intrathecally a composition according to  claim 1  which comprises at least one rAAV expressing an immunoglobulin specific for a Derlin-1-binding region, an antibody construct against neurite outgrowth inhibitor, or ALS enzyme superoxide dismutase 1 (SOD1) and variants thereof, provided the anti-SOD1 antibody is other than an ScFv fragment. 
     
     
         16 . A method for treatment of Parkinson's Disease or related synucleinopathies, said method comprising delivering intrathecally a composition according to  claim 1  which comprises at least one rAAV stock encoding one or more leucine-rich repeat kinase 2 antibody, dardarin (LRRK2) antibody, alpha-synuclein antibody, or DJ-1 (PARK7) antibody. 
     
     
         17 . A method for treatment of multiple sclerosis, said method comprising delivery intrathecally of a composition according to  claim 1  which comprises at least one rAAV stock encoding an immunoglobulin directed against one or more of an a4-integrin, LINGO1, CD20, CD25, IL12, p40+IL23p40, LINGO-1, CD40, and rHIgM22, CD52, IL17, CD19, or SEMA4D. 
     
     
         18 . A method for treatment of infectious disease of the central nervous system, said method comprising delivering a composition according to  claim 1  intrathecally which comprises at least one vector stock encoding an immunoglobulin directed against one of  Mycobacterium tuberculosis, Neisseria meningitides, Streptococcus pneumonia, Listeria monocytogens, Borrelia burdorferia , human immunodeficiency virus, a herpes family viruses, varicella zoster virus, Epstein-Barr virus (EBV), cytomegalovirus, japanese encephalitis, european encephalitis, and/or JC virus. 
     
     
         19 . A method for treatment of prion related diseases, said method comprising delivering a composition according to  claim 1  intrathecally, which composition comprises at least one vector stock encodes an immunoglobulin directed one or more of major prion protein, or PrP Sc . 
     
     
         20 . The method according to  claim 19 , wherein said composition is delivered in the absence of chemical or physical disruption of the blood brain barrier.