The present invention relates to a bioactive agent capable of increasing the intracellular concentration and/or activity of Hsp70 for use in the treatment of a lysosomal storage disease which arise from a defect in an enzyme whose activity is not directly associated with the presence of lysosomal BMP as a co-factor; such as glycogen storage diseases, gangliosidoses, neuronal ceroid lipofuscinoses, cerebrotendinous cholesterosis, Wolman's disease, cholesteryl ester storage disease, disorders of glycosaminoglycan metabolism, mucopolysaccharidoses, disorders of glycoprotein metabolism, mucolipidoses, aspartylglucosaminuria, fucosidosis, mannosidoses, and sialidosis type II.

Methods for the treatment and prevention of laminopathies and diseases characterised by hyperlipidemia through LING complex inhibition are disclosed. In particular, LING complex disruption by expression of dominant-negative LING complex proteins alleviates pathophysiology in Lmna mutation-associated muscular dystrophy, progeria, and dilated cardiomyopathy. In addition, LING complex disruption by expression of dominant-negative LING complex proteins also alleviates pathophysiology in mouse models of atherosclerosis and familial hypercholesterolemia.

The present invention relates to methods and systems for a delay in the onset of early osteogenic markers, a reduction in the hematopoietic potential to form granulocyte units, and a decrease in vascular potential and in cancer-related gene expression. The present invention is a method of down-regulation of GLI1 via CRISPR or siRNA. The present invention indicates that the GLI1 intronic region is critical for the feedback loop and that GLI1 has lineage-specific effects on hESC differentiation. The present invention documents the extent of GLI1 abrogation on early stages of human development and to show that GLI1 transcription can be altered in a therapeutically useful way.

The present invention relates to methods and materials useful for systemically delivering polynucleotides across the blood brain barrier using adeno-associated virus as a vector. For example, the present invention relates to methods and materials useful for systemically delivering α-N-acetylglucosamidinase polynucleotides to the central and peripheral nervous systems, as well as the somatic system. Use of these methods and materials is indicated, for example, for treatment of the lysosomal storage disorder mucopolysaccharidosis IIIB. As another example, the present invention relates to methods and materials useful for systemically delivering N-sulphoglucosamine sulfphohydrolase polynucleotides to the central and peripheral nervous systems, as well as the somatic system. Use of this second type of methods and materials is indicated, for example, for treatment of the lysosomal storage disorder mucopolysaccharidosis IIIA.

The present invention relates to methods and materials useful for systemically delivering polynucleotides across the blood brain barrier using adeno-associated virus as a vector. For example, the present invention relates to methods and materials useful for systemically delivering α-N-acetylglucosamidinase polynucleotides to the central and peripheral nervous systems, as well as the somatic system. Use of these methods and materials is indicated, for example, for treatment of the lysosomal storage disorder mucopolysaccharidosis IIIB. As another example, the present invention relates to methods and materials useful for systemically delivering N-sulphoglucosamine sulfphohydrolase polynucleotides to the central and peripheral nervous systems, as well as the somatic system. Use of this second type of methods and materials is indicated, for example, for treatment of the lysosomal storage disorder mucopolysaccharidosis IIIA.

A composition contains at least one probiotic or enzyme selected from the group consisting of (i) a probiotic having β-glycosidase activity or a β-glycosidase, (ii) a probiotic having esterase activity or an esterase, (iii) a probiotic having both β-glycosidase activity and esterase activity or an enzyme having both β-glycosidase activity and esterase activity, (iv) a first probiotic having β-glycosidase activity and a second probiotic having esterase activity, (v) a probiotic having β-glycosidase activity and an esterase, (vi) a β-glycosidase and a probiotic having esterase activity and (vii) a β-glycosidase and an esterase. The at least one probiotic can form one or more of oleuropein aglycone, elenolic acid, hydroxytyrosol acetate or hydroxytyrosol from oleuropein. The composition can comprise oleuropein. The composition can be for treating or preventing impaired mobility in an older adult; stimulating bone formation and/or inhibiting bone resorption; treating or preventing synovitis in an individual in need or at risk thereof or treating or preventing articular cartilage degradation subsequent to synovitis in an individual having or recovering from synovitis; or preventing or treating cartilage breakdown.

The disclosure provides a guide RNA (gRNA) comprising a DNA-binding domain and a Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated endonuclease protein-binding domain, wherein the DNA-binding domain is complementary to a target domain from a variant NRF2 gene found in a cancer cell but not in a non-cancerous cell. The disclosure also provides nucleic acid sequence encoding the gRNA. The disclosure further provides a method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated endonuclease and a guide RNA that is complementary to a target domain from a variant NRF2 gene in the subject. Methods of treating cancer comprising administering a pharmaceutical composition comprising: a DNA sequence encoding a guide RNA that is complementary to a target domain from a variant NRF2 gene in the subject; and a nucleic acid sequence encoding a Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated endonuclease, are also provided.

Some aspects of this disclosure provide compositions, methods, and kits for improving the specificity of RNA-programmable endonucleases, such as Cas9. Also provided are variants of Cas9, e.g., Cas9 dimers and fusion proteins, engineered to have improved specificity for cleaving nucleic acid targets. Also provided are compositions, methods, and kits for site-specific nucleic acid modification using Cas9 fusion proteins (e.g., nuclease-inactivated Cas9 fused to a nuclease catalytic domain or a recombinase catalytic domain). Such Cas9 variants are useful in clinical and research settings involving site-specific modification of DNA, for example, genomic modifications.

The application is directed to compounds of formulae (IA) and (IB): (IA) and (IB), and their salts and solvates, wherein R.sup.1a, R.sup.2a, .sup.A1, A.sup.2, A.sup.3, A.sup.4, R.sup.1b, R.sup.2b, B.sup.1, B.sup.2, B.sup.3, and G are as set forth in the specification, as well as to methods for their preparation, N pharmaceutical compositions comprising the same, and use thereof for the treatment and/or prevention of, e.g., lysosomal storage diseases, such as Krabbe's disease, and α-synucleinopathies, such as Parkinson's disease.

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The present application provides materials and methods for treating a patient with one or more conditions associated with ANGPTL4 whether ex vivo or in vivo. In addition, the present application provides materials and methods for editing and/or modulating the expression of ANGPTL4 gene in a cell by genome editing.