This invention provides RNA, oligoribonucleotide, and polyribonucleotide molecules comprising pseudouridine or a modified nucleoside, gene therapy vectors comprising same, methods of synthesizing same, and methods for gene replacement, gene therapy, gene transcription silencing, and the delivery of therapeutic proteins to tissue in vivo, comprising the molecules. The present invention also provides methods of reducing the immunogenicity of RNA, oligoribonucleotide, and polyribonucleotide molecules.

The present invention provides, among other things, effective methods and compositions for delivering messenger RNA (mRNA) via rectal delivery. The present invention is, in part, based on unexpected observation that mRNA may be effectively delivered to the circulation, liver, kidney, colon and/or rectum via rectal delivery despite the barriers such as RNase and mucus layer.

Disclosed are methods for treating neurological disorders such as Parkinson's disease (PD) using glutamic acid decarboxylase (GAD) and identifying PD patients that will be most receptive to the method of treating PD. In one aspect, the disclosure provides a method of treating PD in a subject in need thereof, the method comprising: (a) identifying a subject having less than about 10 hours, and preferably less than about 8 hours, of on-time per day; and (b) administering to the subject a composition comprising a therapeutically effective amount of one or more vectors to the subthalamic nucleus of the patient, wherein each vector comprises a nucleic acid sequence encoding glutamic acid decarboxylase (GAD) and wherein the subject's on-time is increased.

Disclosed herein include adeno-associated virus (AAV) acoustic targeting peptides. An AAV comprising the AAV acoustic targeting peptide can exhibit increased transduction at site(s) of focused ultrasound blood-brain barrier opening (FUS-BBBO), increased neuronal tropism, and diminished transduction of peripheral organs. Disclosed herein include recombinant adeno-associated virus (rAAV) comprising an AAV acoustic targeting peptide disclosed herein. Also provided herein include methods of delivering an agent to one or more target brain region(s) of a subject.

Aspects of the disclosure relate to compositions and methods for expressing anti-Vascular endothelial cell growth factor (VEGF) agent in a cell or subject. In some embodiments, the disclosure provides rAAVs comprising a capsid protein (e.g., AAV2 variants, AAV2/3 hybrid variants, AAV8 variants, etc.), and a transgene encoding an anti-VEGF agent (e.g., KH902) and one or more regulatory sequences. In some embodiments, compositions described herein are useful for treating subjects having diseases associated with angiogenesis or aberrant VEGF activity/signaling.

The present invention relates to lentiviral particles which have been pseudotyped with Nipah virus (NiV) fusion (F) and attachment (G) glycoproteins (NiVpp-F/G). Additionally, the present invention relates to truncated NiV-F glycoproteins useful in producing such NiVpp lentiviral particles, as well as to additional variant peptides which enhance activity. Further, the present invention relates to methods of using such lentiviral particles or sequences, for example in the treatment of cancer or CNS disorders.

Provided herein are variant adeno-associated virus (AAV) capsid proteins having one or more modifications in amino acid sequence relative to a parental AAV capsid protein, which, when present in an AAV virion, confer increased infectivity of one or more types of retinal cells as compared to the infectivity of the retinal cells by an AAV virion comprising the unmodified parental AAV capsid protein. Also provided are recombinant AAV virions and pharmaceutical compositions thereof comprising a variant AAV capsid protein as described herein, methods of making these rAAV capsid proteins and virions, and methods for using these rAAV capsid proteins and virions in research and clinical practice, for example in, e.g., the delivery of nucleic acid sequences to one or more ceils of the retina for the treatment of retinal disorders and diseases.

A recombinant adeno-associated virus (rAAV) comprising an AAVhu68 capsid and a vector genome comprising a lysosomal beta-galactosidase gene (for example, galactosidase beta 1 gene, GBL1) is provided (i.e., rAAVhu68.GBL1). Also provided a composition containing an effective amount of rAAVhu68.GBL1 to ameliorate symptoms of GM1 gangliosidosis, including, e.g., increased average life span, decreased need for feeding tube, reduction in seizure incidence and frequency, reduction in progression towards neurocognitive decline and/or improvement in neurocognitive development.

The present invention relates to expression constructs and viral and other vectors for the treatment and/or prevention of chronic pain.

A gene therapy vector comprising an expression cassette coding for a mammalian apolipoprotein E that has a residue other than arginine at at least one of positions 112, 136, or 158, but is not a mammalian apolipoprotein E that has R112, R136 and R158 or a mammalian apolipoprotein E that has C112, R136 and C158, or coding for an antibody that binds to APOE4 or disrupts the binding of APOE to heparan sulfate proteoglycans, and methods of using the vector, are provided.