Abstract: Aspects of the disclosure relate to compositions and methods useful for treating neurological diseases and disorders. In some embodiments, the disclosure provides a method for treating a neurological disease or disorder comprising administration of both a viral vector comprising interfering nucleic acids (e.g., artificial miRNAs) and a viral vector comprising a CYP46A1 protein. In some embodiments, the disclosure provides a method for treating Huntington's disease comprising administration of both a viral vector comprising interfering nucleic acids (e.g., artificial miRNAs) targeting the huntingtin gene (HTT) and a viral vector comprising a CYP46A1 protein. In some embodiments, the viral vector comprises a modified viral capsid, such as for preferentially targeting cells in the CNS or PNS.

Abstract: The present invention relates to methods of enriching target single-stranded nucleic acids in a mixed population of single-stranded nucleic acids. The method involves protecting the target single-stranded nucleic acids and using a 5? exonuclease to digest the non-target single-stranded nucleic acids. The invention also relates to methods of cloning target single-stranded nucleic acids into vectors, and to associated compositions and kits.

Abstract: This invention provides nanoparticles containing protein-polynucleotide complexes and methods of manufacture and methods of their use. These particles, when administered to a subject in need, are capable of delivering these complexes to target cells and target intracellular locations where they can perform a therapeutic function. In some embodiments, this therapeutic function includes gene editing, induction of gene skipping, and regulation of gene expression. The instant nanoparticles are generally formed by designing and synthesizing the polynucleotide to according to its intended function, combining it with a protein selected for its substrate specificity and enzymatic function in a manner to form a polynucleotide-protein complex, encapsulating the complexes by dispersion into a water-insoluble surfactant system, optionally adding a targeting ligand, and stabilizing the nanoparticles by crystallization of the ligand to the surface of the nanoparticles.

Abstract: The present invention relates to a substantially homogenous population of a rational polyploid adeno-associated virus (AAV) virons that cross the blood brain barrier (BBB), where the rational polyploid comprises a VP3 viral structural protein from any AAV serotype that cross the BBB. In some embodiments, the rational polyploid crosses the BBB upon systemic or intrathecal administration to a subject. In some embodiments, a rational polyploid AAV virion comprises at least one VP1 and/or VP2 viral structural protein in addition to the VP3 protein. In some embodiments, the VP3 capsid protein is from a non-human primate, and in some embodiments the VP3 capsid protein is a AAV rhesus monkey serotype. In specific embodiments, rational polyploid AAV virion comprises a VP1 capsid protein from AAV8, and at least a VP3 capsid protein from any AAV serotype that cross the BBB.

Abstract: Provided herein are purification, production and manufacturing methods for recombinant viral vector particles such as recombinant adeno-associated viral (rAAV) vector particles substantially free of empty viral particles; a population of recombinant adeno-associated vims (rAAV) particles purified using the method described herein, and a pharmaceutical composition comprising the purified rAAV.

Abstract: Aspects described herein relate to stable cell line for recombinant viral vector (e.g., recombinant adeno associated viral vector) production comprising at least one inducible promoter operatively linked to a heterologous gene that encodes a toxic protein. Methods for making stable cell lines, and methods for viral vector production are further provided herein.

Abstract: Aspects described herein relate to stable cell line for recombinant viral vector (e.g., recombinant adeno associated viral vector) production comprising at least one inducible promoter operatively linked to a heterologous gene that encodes a toxic protein. Methods for making stable cell lines, and methods for viral vector production are further provided herein.

Abstract: The present invention relates to forskolin-inducible and hypoxia-inducible cis-regulatory elements, promoters and vectors, and methods of their use.

Abstract: Disclosed herein are various optimized nucleic acids encoding the fukutin-related protein (FKRP). Recombinant vectors comprising the optimized nucleic acid (e.g. operatively linked to a muscle specific promoter), such as recombinant adeno-associated virus vectors, for expressing the protein (e.g. in skeletal and cardiac muscle), and therapeutic compositions contains the vectors are also disclosed. Therapeutic methods of administration of the vectors to a subject for the treatment of a subject with a dystroglycanopathy disorder (e.g., limb-girdle muscular dystrophy 2I) are also disclosed.

Abstract: Aspects of the disclosure relate to compositions and methods useful for treating neurological diseases and disorders. In some embodiments, the disclosure provides a method for treating a neurological disease or disorder comprising administration of both a viral vector comprising interfering nucleic acids (e.g., artificial miRNAs) and a viral vector comprising a CYP46A1 protein. In some embodiments, the disclosure provides a method for treating Huntington's disease comprising administration of both a viral vector comprising interfering nucleic acids (e.g., artificial miRNAs) targeting the huntingtin gene (HTT) and a viral vector comprising a CYP46A1 protein. In some embodiments, the viral vector comprises a modified viral capsid, such as for preferentially targeting cells in the CNS or PNS.

Abstract: The present invention provides a plurality of synthetic nucleic acid comprising (a) a nucleic acid sequence containing at least one unique regulatory element (URE); wherein the URE comprises at least one regulatory element and a plurality of unique barcodes associated with the at least one regulatory element; and (b) a nucleic acid sequence encoding an transcribable reporter sequence, wherein each barcode is between 12-35 nucleotides in length and have a GC content between 25-65%. URE can be one regulatory element or a combination of regulatory elements. Libraries of expression vectors and plasmids expressing the plurality of synthetic nucleic acids are also provided herein. Additional aspects described herein are methods for identifying the strength of a unique regulatory element in vivo or in vitro using the synthetic nucleic acids or libraries expressing the same.

Abstract: The present invention relates to methods of administration of rAAV vectors in a single administration method comprising a series of sub-administrations of sub-doses of rAAV vectors. The present invention also relates to rAAV vectors comprising cardiac-specific promoters, cardiac-cell specific promoters, multi-cell cardiac specific promoters, and elements thereof. The invention also relates to rAAV vectors, pharmaceutical compositions and uses thereof in methods for treating cardiovascular disease, heart diseases and heart failure in subjects in need thereof.

Abstract: Aspects of the disclosure relate to compositions and methods useful for treating Huntington's disease. In some embodiments, the disclosure provides interfering nucleic acids (e.g., artificial miRNAs) targeting the huntingtin gene (HTT) and methods of treating Huntington's disease using the same. Accordingly, in some aspects, the disclosure provides an isolated nucleic acid comprising or encoding the sequence set forth in any one of SEQ ID NOs: 1-22.

Abstract: The present invention relates to regulatory nucleic acid sequences, in particular NS-specific promoters, cell specific promoters, multi-cell specific promoters, and elements thereof. The invention also relates to expression constructs, vectors, virions, pharmaceutical compositions and cells comprising such promoters and to methods of their use. The regulatory nucleic acid sequences are of particular utility for gene therapy applications.

Abstract: The present invention relates to the use of a regulatory nucleic acid sequences that are able to regulate gene expression in eukaryotic cells and which are responsive to the unfolded protein response (UPR). There are disclosed regulatable introns and UPR-inducible promoters, which are able to regulate gene expression. There are also disclosed recombinant expression constructs comprising such regulatory nucleic acid sequences, whereby expression of the encoded expression product can be induced by invoking the unfolded protein response (UPR) in a eukaryotic cell containing the construct, methods of using such constructs and associated vectors, cells and suchlike.

Abstract: The present invention relates to regulatory nucleic acid sequences, in particular muscle-specific promoters, elements thereof, and other such nucleic acid sequences, that are capable of enhancing muscle-specific expression of genes. The invention also relates to expression constructs, vectors and cells comprising such muscle-specific regulatory nucleic acid sequences, and to methods of their use. The regulatory nucleic acid sequences are of particular utility for gene therapy applications, but also find utility in other areas such as bioprocessing and biotechnology.

Abstract: The present invention relates to forskolin-inducible and hypoxia-inducible cis-regulatory elements, promoters and vectors, and methods of their use.

Abstract: Disclosed herein are methods of treating a toxicity in a subject receiving recombinant viral vector, such as a recombinant adeno-associated viral AAV (rAAV) vector comprising co-administration of an antibiotic and a viral vector. In one embodiment, the antibiotic is a tetracycline or macrolide family member. Also provided herein are compositions comprising an antibiotic and a viral vector.

Abstract: The present invention relates to regulatory nucleic acid sequences, in particular CNS—specific promoters, and elements thereof. The invention also relates to expression constructs, vectors, virions, pharmaceutical compositions and cells comprising such promoters and to methods of their use. The regulatory nucleic acid sequences are of particular utility for gene therapy applications.

Abstract: The technology described herein is directed to systems and methods for synthetic regulatory sequence design or production. In several aspects described herein are methods of designing and optionally synthesizing shortened or otherwise modified polynucleotide sequences from polynucleotide sequences with transcriptional regulatory functionality. In other aspects described herein are isolated nucleic acid modules and viral vectors, comprising said shortened or otherwise modified polynucleotide as designed or synthesized herein.