Adeno-associated virus based vectors for gene therapy of retinal and central nervous system

摘要

Recombinant adeno-associated virus (rAAV) improved (e.g., raavrh8r rAAV2, Gene Therapy, etc.) for improved Eye Disorders or disorders of the CNS, where the rAAV, comprising one or more amino acid substitutions that interact with heparan sulfate proteoglycan.Methods to improve the transduction of retinal cells and Methods for treating ocular Diseases with improved Particle compositions of rAAV. Recombinant adeno-associated virus (rAAV) improved (EG, rAAV2, raavrh8r, etc.) for gene therapy improved CNS disorders.Methods to supply the rAAV in the CNS, Methods for treating disorders of the CNS with improved rAAV Particle compositions, and Kits for supplying the rAAV in the CNS and / or treat a disorder of the CNS.Claim 47: a system for the supply of a subretinal vector in an eye of an individual which comprises: a) a composition comprising an effective amount of particles of rAAV.Where (i) a Protein capsid of the rAAV particles comprising one or more amino acid substitutions in one or more positions that interact with heparan sulfate proteoglycan or in one or more positions that correspond to amino acids 484 487, 532, or 585 588.Numbering is based on the numbering of VP1 of AAV2, and (ii) the Vector comprising a Nucleic Acid encoding a heterologous polypeptide Therapeutic or therapeutic RNA and at least one terminal of AAV Replication; and (b) a device for Supply of subretinal rAAV.The system of claim 48: 47 claims where the device includes a Cannula and a fine syringe diameter, where the Thin diameter Gauge Cannula is 27 to 45.73. The system of claim claim 47 - 72 where heterologous Nucleic Acid encoding a polypeptide selected from the group consisting of an Antioxidant, a neurotrophic factor, a factor antiapoptu00f3tico, an anti angiogenic factor and a factor Antii Nflamatorio.74: the system of claim claim 47 - 73 where heterologous Nucleic Acid encoding a polypeptide selected from the group consisting of: PRPH2, RPE65, AIPL1, GUCY2D, LCA5, CRX, CEP290, Myo 7a, Bugle, ABCA4, RDH12, IMPDH1, CRB1, LRAT, nmnat1, TULP1, RP2 and RPGR, MerTK, rpgrip CNGA3 and CNGB3, GNAT2, CNTF, GDNF, FGF2, PEDF, EPO, BCL 2, BCL X, NFkB,Endostatin. Angiostatin, sFlt, spdgf - R, il10, anti ili7, sil17r, IL1 ra, anti TGFb and iL4.310: a Vindication of rAAV Particle comprising a aavrh8r capsid Protein, where the Protein capsid aavrh8r comprising one or more amino acid substitutions.Where one or more amino acid substitutions increase the Union of rAAV Particle of the heparan sulfate proteoglycan compared with a Particle comprising an AAV capsid Protein aavrh8r natural type or where the replacement of one or more amino acids in an Or more positions that correspond to amino acids 484 487, 532, and 585 588Numbering is based on the numbering of VP1 AAV2.Claim 317: a method for Increasing the Union of a rAAV Particle comprising a Protein capsid aavrh8r the heparan sulfate proteoglycan.That involves Introducing one or more amino acid substitutions in the Protein capsid where one or more amino acid substitutions increase the Union of rAAV Particle of the heparan sulfate proteoglycan compared with a Particle of AAV comprising a Protein of chap. Side of aavrh8r natural type.Claim 367: a method to improve the expression of a heterologous nucleic acid after intravitreal delivery of rAAV particles of the eye of an individual Understanding method incorporating one or more amino acid substitutions in AAV capsid Protein a or m More positions that interact with heparan sulfate proteoglycan or in one or more positions forThe amino acid n 484 487, 532, or 585 588, numbering based on the numbering of VP1 of AAV2; where the particle consists of rAAV capsid Protein of rAAV and rAAV vector comprising a heterologous nucleic acid and at least one terminal Repeat of AAV.