The present disclosure provides methods and compositions for enhanced editing of genomic DNA. For example, in some embodiments, a subject method is a method of editing genomic DNA of a eukaryotic cell and the method includes introducing into a eukaryotic cell a composition comprising: (a) a linearized non-homologous DNA composition and (b) a genome targeting composition (which includes a genome editing endonuclease, or a nucleic acid encoding the genome editing endonuclease). In some cases in which the genome editing endonuclease is a CRISPR/Cas endonuclease, the genome targeting composition can also include a corresponding CRISPR/Cas guide RNA.

Disclosed herein are compositions and methods of treating disclosure provides for compounds for use in treating Mitochondrial Neurogastrointestinal Encephalopathy Syndrome (MNGIE). In some embodiments, the compounds have cell penetrating activity and thymidine phosphorylase activity. In certain embodiments, the compounds disclosed herein comprise: a) at least one cell-penetrating peptide (CPP) moiety; and b) a thymidine phosphorylase, or an active fragment or analog thereof (TP), wherein the CPP is coupled, directly or indirectly, to TP.

The present invention relates to methods of regulating G protein activity, and related methods for the treatment of therapeutic conditions, for example retinal degeneration, by transforming a cell with a bistable opsin to activate a G protein, and provide a phototransduction response.

The disclosure features compositions and methods for the treatment of sensorineural hearing loss and auditory neuropathy, particularly forms of the disease that are associated with a mutation in otoferlin (OTOF), by way of OTOF gene therapy. The disclosure provides a variety of compositions that include a first nucleic acid vector that contains a polynucleotide encoding an N-terminal portion of an OTOF isoform 5 protein and a second nucleic acid vector that contains a polynucleotide encoding a C-terminal portion of an OTOF isoform 5 protein. These vectors can be used to increase the expression of OTOF in a subject, such as a human subject suffering from sensorineural hearing loss.

Disease model pigs produced by nuclear transplantation, disease model pigs exhibiting stable phenotypes and production methods thereof are provided. Chimeric pigs for producing disease model pigs exhibiting stable phenotypes, genital glands thereof, and germ cells thereof are also provided. A method for producing a genetically modified disease model pig, includes: (a) transplanting a nucleus of a genetically modified cell into cytoplasm of an egg; (b) developing an obtained clonal embryo in a womb of a female pig to obtain an offspring; and mating the obtained offspring or having the offspring undergo sexual reproduction to further obtain the genetically modified offspring as a disease model pig.

Provided herein are compositions that include at least two different nucleic acid vectors, where each of the at least two different vectors includes a coding sequence that encodes a different portion of an otoferlin protein, and the use of these compositions to treat hearing loss in a subject.

The present invention provides methods and compositions for inducing differentiation of Müller glial cells into rod photoreceptors through a two-step process of inducing Müller glial cell proliferation by increasing WNT signaling effectors in the Müller glial cell and then directed differentiation into a rod photoreceptor through activation of rod-specific photoreceptor genes. The methods and compositions are useful in a method of treating vision loss or impairment due to photoreceptor loss. The present invention also provides methods for treating vision loss or impairment in a subject comprising (a) administering to the subject a therapeutically effective amount of a Müller glial (MG) cell proliferation agent; and (b) a period of time after the administering of step (a), administering to the subject a therapeutically effective amount of a MG cell differentiation agent.

Described herein are nucleic acid molecules and complexes useful as i-switch pH reporters that have increased sensitivities as a pH reporter and have alternate pH reporting capacity ranges. Aspects of the disclosure relate to a method for determining pH comprising providing a nucleic acid complex comprising: a first single-stranded nucleic acid molecule comprising the sequence C.sub.nXC.sub.nYC.sub.nZC.sub.n (SEQ ID NO. 6) wherein C is cytosine; X, Y and Z are each one or more of adenine, thymine, guanine, or combinations thereof; and n is greater than or equal to 2; and wherein at least 2 cytosine residues of the first single-stranded nucleic acid molecule are modified; and a second single-stranded nucleic acid molecule that is partially or fully complementary to the first single-stranded molecule, wherein a first label is conjugated to the first single-stranded nucleic acid molecule or the second single-stranded nucleic acid molecule; and wherein the first label is capable of producing a signal, wherein the intensity of the signal varies as a function of the conformation of the nucleic acid complex; and measuring the intensity of the signal and determining the pH from the measured signal.

The present disclosure provides enzyme replacement therapy using gene therapy vectors, such as adeno-associated virus (AAV) vectors expressing human Cystathionine Beta-Synthase (CBS) to reduce the amount of serum homocysteine (Hcy) and increase the amount of downstream metabolites, such as cystathionine and cysteine (Cys), which can be used for treatment of diseases, such as homocystinuria and homocysteine remethylation disorders.

The present disclosure relates generally to compounds comprising oligonucleotides complementary to a cystic fibrosis transmembrane conductance regulator (CFTR) RNA transcript. Certain such compounds are useful for hybridizing to a CFTR RNA transcript, including but not limited to a CFTR RNA transcript in a cell. In certain embodiments, such hybridization results in modulation of splicing and/or expression of the CFTR transcript. In certain embodiments, such compounds are used to treat one or more symptoms associated with Cystic Fibrosis.