The present disclosure provides a Cas9 heterodimer, as well as nucleic acids encoding the Cas9 heterodimer, and host cells comprising the nucleic acids. The present disclosure provides a system that includes a Cas9 heterodimer of the present disclosure and at least one of: a Cas9 guide RNA, and a dimerizing agent. A Cas9 heterodimer of the present disclosure is useful in a wide variety of applications, which are also provided.

Compositions and methods for down-regulating genes through oral administration of RNAi molecule encapsulated in plant cells are provided.

Engineered CRISPR-Cas9 nucleases with altered and improved PAM specificities and their use in genomic engineering, epigenomic engineering, and genome targeting.

A log of molecular events experienced by a cell and timing indicators for those events are stored in existing polynucleotides through a process of creating a double strand break (“DSB”) in a polynucleotide and inserting a new polynucleotide sequence by repairing the DSB with homology directed repair (“HDR”). The presence, order, and number of new polynucleotide sequences provides a log of events and timing of those events. Cellular mechanisms for creating the DSB and/or repairing with HDR are regulated by intra- or extra-cellular signals. When the log is created in the DNA of a cell, the changes may be heritably passed to subsequent generations of the cell. A correlation between the cellular signals and sequence of inserted HDR templates allows for identification of events and the timing experienced by the cell.

Compounds, compositions and methods are provided for modulating the expression and function of small non-coding RNAs. The compositions comprise oligomeric compounds, targeted to small non-coding RNAs. Methods of using these compounds for modulation of small non-coding RNAs as well as downstream targets of these RNAs and for diagnosis and treatment of disease associated with small non-coding RNAs are also provided.

Provided herein is chitosan dually derivatized with arginine and gluconic acid; and methods of making and using the same, e.g., for gene delivery in vivo.

The invention involves inducing 3-50 or more mutations (e.g., any whole number between 3 and 50 of mutations, with it noted that in some embodiments there can be up to 16 different RNA(s), e.g., sgRNAs each having its own a promoter, in a vector, such as AAV, and that when each sgRNA does not have its own promoter, there can be twice to thrice that amount of different RNA(s), e.g., sgRNAs, e.g., 32 or even 48 different guides delivered by one vector) in transgenic Cas9 eukaryotes to model genetic disease, e.g. cancer. The invention comprehends testing putative treatments with such models, e.g., testing putative chemical compounds that may be pharmaceutically relevant for treatment or gene therapy that may be relevant for treatment, or combinations thereof. The invention allows for the study of genetic diseases and putative treatments to better understand and alleviate a genetic disease or a condition, e.g., cancer.

The present disclosure provides oligomeric compounds. The present disclosure provides metabolically stable linkers that do not rapidly degrade in vivo. In certain embodiments, the present disclosure provides metabolically stable linkers for use in attaching a conjugate group to an oligonucleotide.

Delivery devices, systems, and methods related thereto may be used in humans for spinal delivery of cells, drugs or vectors. Thus, the system enables subpial delivery, which leads to a near complete spinal parenchymal AAV9-mediated gene expression or ASO distribution in both white and grey matter.

A lipidated secondary antibody is disclosed. Particles comprising same are also disclosed.