A rAAV for treatment of a disorder associated with a deficiency in hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme levels via gene delivery is provided herein. Also provided herein is a method for treating disorder associated with a deficiency in hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme levels by direct delivery to dopaminergic neurons. Correction of Lesch-Nyhan disease may be monitored by assessing dopamine metabolism levels and/or imaging for the presence of dopaminergic cell bodies.

There are provided a recombinant cell that enables efficient production of protein, a method for producing the same, and a method for producing protein by using the cell. The cell is a mammalian cell having integrated therein 3 or more expression units containing an exogenous gene of interest, wherein gap elements are provided among multiple expression units, wherein the gap elements are designed to have chain lengths of 0.5 kbp or more, and the gap elements are mutually different sequences. Such a cell can produce recombinant protein stably for a long period and, especially, can show a strong positive linear correlation between the number of genes of interest introduced therein and the expression levels.

Aspects of the disclosure relate to complexes comprising a muscle-targeting agent covalently linked to a molecular payload. In some embodiments, the muscle-targeting agent specifically binds to an internalizing cell surface receptor on muscle cells. In some embodiments, the molecular payload promotes the expression or activity of a functional dystrophin protein. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide, e.g., an oligonucleotide that causes exon skipping in a mRNA expressed from a mutant DMD allele.

A gene of interest and the gene encoding hypoxanthine-aminopterin-thymidine (HPRT) can be co-targeted for Casp9 nuclease-mediated editing or alteration in a cell. Based on whether the HPRT gene is altered to encode a non-functional protein, or is not so-altered, the co-targeted cells can be selected and counter-selected. HPRT co-targeting can be used to sequentially disrupt as many genes of interest as cell viability permits.

Aspects of the disclosure relate to molecular payloads that modulate the expression or activity of genes involved in muscle growth and maintenance (e.g., MSTN, INHBA, ACVR1B, MLCK1, ACVR1, FBXO32, TRIM63, MEF2D, KLF15, MED1, MED13, and/or PPP1R3A), and complexes comprising a muscle-targeting agent covalently linked to such molecular payloads. In some embodiments, the muscle-targeting agent specifically binds to an internalizing cell surface receptor on a muscle cell (e.g., a cardiac muscle cell, a smooth muscle cell, a skeletal muscle cell). In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.

Provided herein are oligomeric compounds comprising a bicycle ligand and a modified oligonucleotide. This compound may comprise a bicycle ligand as the cell-targeting moiety, and may also comprise a conjugate linker to connect the bicycle ligand and modified oligonucleotide. This compound may be used in conjunction with a pharmaceutically acceptable salt.

Modified macrophage immune cells are provided for treatment of cancer and other diseases.

The present invention relates to lipid compounds and uses thereof. In particular, the compounds include a class of cationic lipids having an amine moiety, such as an amino-amine or an amino-amide moiety. The lipid compounds are useful for in vivo or in vitro delivery of one or more agents (e.g., a polyanionic payload or an antisense payload, such as an RNAi agent).

Aspects of the disclosure relate to complexes comprising a muscle-targeting agent covalently linked to a molecular payload. In some embodiments, the muscle-targeting agent specifically binds to an internalizing cell surface receptor on muscle cells. In some embodiments, the molecular payload promotes the expression or activity of a functional dystrophin protein. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide, e.g., an oligonucleotide that causes exon skipping in a mRNA expressed from a mutant DMD allele.

The present invention relates to lipid compounds and uses thereof. In particular, the compounds include a class of cationic lipids having an amine moiety, such as an amino-amine or an amino-amide moiety. The lipid compounds are useful for in vivo or in vitro delivery of one or more agents (e.g., a polyanionic payload or an antisense payload, such as an RNAi agent).