The present invention relates to promoters that function specifically or preferentially in the liver. These promoters are capable of enhancing liver-specific expression of genes. The invention also relates to expression constructs, vectors and cells comprising such liver-specific promoters, and to methods of their use. The present invention future relates to adeno-associated virus (AAV) gene therapy vectors comprising the liver-specific promoters, therapeutic agents comprising the liver-specific promoters, and methods using the same.

The present invention provides methods, immunoglobulin compositions and vector constructs as a general approach to provide episomal based immune protection from the 2019 novel coronavirus (COVID-19), its variants/mutants and other pandemic and even non-pandemic viruses. The immunoglobulin compositions include the heavy chain variable, diversity and joining (VDJ or Variable Heavy Region genes) segment immunoglobulin DNA and/or polypeptide sequence from humans identified to have developed high affinity immunoglobulins (ideally antibodies with nanomolar to picomolar dissociation constants to virus proteins with additional emphasis on cell surface proteins and further emphasis on the Spike protein as related to COVID-19) against the virus of interest and either to use the exact immunoglobulin composition identified from the donor or to combine that variable immunoglobulin region for both heavy and light chains with a non-divergent well-conserved amino acid sequence for the constant regions especially, Hinge region, Constant Heavy 2 (C.sub.H2) and Constant Heavy 3 (C.sub.H3) for the immunoglobulin heavy chain polypeptide with optional use of donor based Constant Heavy 1 (C.sub.H1) or non-divergent well conserved C.sub.H1 heavy chain constant region and optional use of hinge region peptides. The immunoglobulin light chain will use either entirely donor based amino acid sequence or donor based light chain variable and joining (VJ or Variable light region genes) segments immunoglobulin polypeptide sequence with a well-conserved non-divergent constant light (C.sub.L) chain region for immunoglobulin Kappa locus (κ) or immunoglobulin lambda locus (λ) light chain. The resulting antibodies can either be used as a monoclonal or polyclonal mix of (Immunoglobulin Class G subclass1) IgG1, IgG3 and other subclasses, IgA1 monomer and IgA2 monomer and dimeric IgA1 (dIgA1) immunoglobulins (as identified by the potency of associated memory B-cells) to be expressed via intramuscular administration, intravenous or proximal to lymph nodes. The immunoglobulins will be expressed in the vaccine/immunization recipient via an episome. The vector will be ideally delivered in a recombinant Adeno Associated Virus (rAAV) with preference for AAV serotype 8 (AAV8) containing a single-stranded Deoxyribonucleic acid (ssDNA) non-viral vector or lentivirus virion containing double stranded DNA as a non-viral vector. A single non-viral vector will code for the entire immunoglobulin and J-chain expression for dIgA1 where expression will occur with a single start codon and stop codon for the amino acid sequence and in some embodiments a second start codon for J chain expression. The specific DNA

There is described a nucleic acid molecule comprising a nucleotide sequence encoding a functional dystrophin protein. Also described is a vector, a host cell and a pharmaceutical composition comprising the nucleic acid molecule; use of the nucleic acid molecule in therapy, such as in the treatment of a muscular dystrophy; and a method of treating muscular dystrophy, the method comprising administering a therapeutically effective amount of the nucleic acid molecule to a patient suffering from a muscular dystrophy.

Methods are described for predicting ancestral sequences for viruses or portions thereof. Also described are predicted ancestral sequences for adeno-associated virus (AAV) capsid polypeptides. The disclosure also provides methods of gene transfer and methods of vaccinating subjects by administering a target antigen operably linked to the AAV capsid polypeptides.

Provided herein are methods for the treatment of bladder dysfunction, including detrusor hyperreflexia and detrusor external sphincter dyssynergia, fecal incontinence, and/or sexual dysfunction in an individual via the use of stably expressed light-responsive opsin proteins capable of selective hyperpolarization or depolarization of the neural cells that innervate the muscles responsible for physiologic functioning of urinary bladder, external urinary sphincter, external anal sphincter, and the male and female genitalia.

This invention relates to viral vectors for delivery of alpha-L-iduronidase to the cornea of a subject and methods of using the same for treatment and prevention of corneal clouding and blindness in a subject due to mucopolysaccharidosis I.

Disclosed herein are compositions and methods for treating diseases characterized by expanded microsatellite repeats by impeding or inhibiting transcription of expanded microsatellite repeats.

Methods and compositions are provided herein for assessing CRISPR/Cas-mediated non-homologous end joining (NHEJ) activity and/or CRISPR/Cas-induced recombination of a target genomic locus with an exogenous donor nucleic acid in vivo and ex vivo. The methods and compositions employ cells and non-human animals comprising a Cas expression cassette such as a genomically integrated Cas expression cassette so that the Cas protein can be constitutively available or available in a tissue-specific or temporal-specific manner. Methods and compositions are also provided for making and using these non-human animals, including use of these non-human animals to assess CRISPR/Cas activity in vivo via adeno-associated virus (AAV)-mediated delivery of guide RNAs to the non-human animals.

The invention provides gene therapy vectors, such as adeno-associated vims (AAV) vectors, expressing a miniaturized human micro-dystrophin gene and method of using these vectors to express micro-dystrophin in skeletal muscle s including diaphragm and cardiac muscle and to protect muscle fibers from injury, increase muscle strength and reduce and/or prevent fibrosis in subjects suffering from muscular dystrophy.

Human anti-AAV capsid polyclonal antibody conformational epitopes including those of neutralizing antibodies are provided. The epitopes can be recognized by human anti-AAV2 or other AAV strain-derived capsid polyclonal antibodies. One or more of the epitopes may be mutated to form AAV2 and other AAV strain-derived capsids that can escape antibody neutralization. Methods of identifying human anti-AAV capsid polyclonal antibody conformational epitopes are also provided.