Abstract: Described herein are compositions, vectors, cells, methods, and kits that provide cell data recorder systems for recording cell states. The cell data recorder systems allow for the recording of both the presence and duration of one or more stimuli in a programmable, reproducible, and multiplexable manner. These cell data recorder systems employ a nucleic acid programmable DNA binding protein, such as a Cas9 nuclease, or a fusion protein comprising a nucleic acid programmable DNA binding domain and a nucleic acid editing domain to introduce recordable changes in the genome of a cell or in a plasmid within the cell.

Abstract: The present invention features improved compounds, especially methods of identifying patients having cancer using biomarkers (e.g., PDE3A, SLFN12 and/or CREB3L1) that correlate with drug sensitivity and consequently treating a stratified patient population with an agent of the invention (e.g., Compounds 1-6 disclosed herein).

Abstract: The present disclosure provides methods for profiling spatiotemporal gene expression, including methods for profiling spatiotemporal gene expression in vivo in a subject. The present disclosure also provides methods for profiling the role of post-transcriptional modification in spatiotemporal gene expression, methods for studying the role of spatiotemporal gene expression in the development or progression of a disease or disorder, methods for screening for an agent capable of modulating spatiotemporal gene expression, methods for diagnosing a disease or disorder in a subject, and methods for treating a disease or disorder in a subject. Oligonucleotide probes useful in the methods described herein are also provided by the present disclosure. The present disclosure also provide kits comprising the oligonucleotide probes disclosed herein. Systems for profiling spatiotemporal gene expression are also provided by the present disclosure.

Abstract: The present disclosure relates to compositions and methods for the diagnosis and treatment or prevention of proteinopathies, particularly MUC1-associated kidney disease (ADTKD-MUC1 or MKD), Retinitis Pigmentosa (e.g., due to rhodopsin mutations), autosomal dominant tubulo-interstitial kidney disease due to UMOD mutation(s) (ADTKD-UMOD), and other forms of toxic proteinopathies resulting from mutant protein accumulation in the ER or other secretory pathway compartments and/or vesicles, among others. The disclosure also identifies and provides TMED9-binding agents as capable of treating or preventing proteinopathies of the secretory pathway, and further provides methods for identifying additional TMED9-binding agents.

Abstract: The subject matter disclosed herein is generally directed to detecting and modulating novel gene signatures for the treatment and prognosis of cancer. The novel gene signatures predict overall survival in cancer and can be targeted therapeutically. Specifically, disclosed is a resistance program identified by a comprehensive single-cell profiling study in melanoma patients, which was validated in two large validation cohorts. Using a large-scale in silico prediction, CDK4/6 inhibitors were identified as a class of drugs that may reverse this resistance program. These predictions were validated in melanoma cell lines, patient-derived co-culture models, and melanoma in vivo models, which show that the combination of abemaciclib and immune checkpoint blockade (ICB) overcome intrinsic drug resistance. The present invention provides for detecting an immunotherapy resistance signature and modulating the signature with CDK4/6 inhibition.

Abstract: The present disclosure relates to methods aimed towards non-invasive targeted genomic and epigenomic sequencing of spatially-defined cellular or subcellular region. More particularly, the present disclosure relates to methods of using photoselection to achieve non-invasive targeted genomic and epigenomic sequencing of spatially-defined cellular or subcellular regions, via the use of light-activated probes.

Abstract: This invention relates generally to compositions and methods for modulating complement component 3 (C3) activity or expression to treat, control or otherwise influence tumors and tissues, including cells and cell types of the tumors and tissues, and malignant, microenvironmental, or immunologic states of the tumor cells and tissues. The invention also relates to methods of diagnosing, prognosing and/or staging of tumors, tissues and cells.

Abstract: The embodiments disclosed herein utilized RNA targeting effectors to provide a robust CRISPR-based diagnostic with attomolar sensitivity. Embodiments disclosed herein can detect broth DNA and RNA with comparable levels of sensitivity and can differentiate targets from non-targets based on single base pair differences. Moreover, the embodiments disclosed herein can be prepared in freeze-dried format for convenient distribution and point-of-care (POC) applications. Such embodiments are useful in multiple scenarios in human health including, for example, viral detection, bacterial strain typing, sensitive genotyping, and detection of disease-associated cell free DNA.

Abstract: The present invention features methods for characterizing mutational profiles in patients with bladder cancer.

Abstract: The present disclosure provides compositions and methods for conducting prime editing of a target DNA molecule (e.g., a genome) that enables the incorporation of a nucleotide change and/or targeted mutagenesis. The nucleotide change can include a single-nucleotide change (e.g., any transition or any transversion), an insertion of one or more nucleotides, or a deletion of one or more nucleotides. More in particular, the disclosure provides fusion proteins comprising nucleic acid programmable DNA binding proteins (napDNAbp) and a polymerase (e.g., reverse transcriptase), which is guided to a specific DNA sequence by a modified guide RNA, named an PEgRNA.

Abstract: The present disclosure provides systems, compositions, and methods for simultaneously editing both strands of a double-stranded DNA sequence at a target site to be edited. In some aspects, the systems comprise a first and second prime editor complex, wherein each of the first and second prime editor complexes comprises (1) a prime editor comprising (i) a nucleic acid programmable DNA binding protein (napDNAbp), and (ii) a polypeptide having an RNA-dependent DNA polymerase activity; and (2) a pegRNA comprising a spacer sequence, gRNA core, a DNA synthesis template, and a primer binding site, wherein the DNA synthesis template encodes a desired DNA sequence or a complement thereof, wherein the desired DNA sequence and the complement thereof form a duplex comprising an edited portion which integrates into the target site to be edited. In some aspects, the systems comprise a first, second, third, and fourth prime editor complex, each comprising a prime editor and a PEgRNA.

Abstract: Disclosed are locational or positional methods concerning CRISPR-Cas systems, and apparatus therefor.

Abstract: Some aspects of this disclosure relate to strategies, systems, methods, compositions, and kits that are useful for production (e.g., evolution) of cytidine deaminase protein variants that are characterized by increased soluble expression and/or stability relative to the wild-type cytidine deaminase protein from which they are evolved. In some embodiments, evolved cytidine deaminase variants described by the disclosure are useful for incorporation into targeted nucleic acid editing proteins, for example in fusion proteins with a Cas9 domain or variant thereof.

Abstract: Provided are methods and compositions for treating cancer in a subject in need thereof. One of the top gene products in glioblastoma multiforme (GBM) is KLRB1 (also known as CD161), a C-type lectin protein that binds to CLEC2D. Binding of CLEC2D to the KLRB1 receptor inhibits the cytotoxic function of NK cells as well as cytokine secretion. KLRB1 is only expressed by small subpopulations of human blood T cells, and consequently little is known about the function of this receptor in T cells. However, preliminary data demonstrate that KLRB1 expression is induced in T cells within the GBM microenvironment. In an exemplary embodiment, a method is provided comprising administering an agent capable of blocking the interaction of KLRB1 with its ligand. The agent may comprise an antibody or fragment thereof, which may bind KLRB1 or CLEC2D.

Abstract: Embodiments disclosed herein provide methods of using somatic mutations in mitochondrial genomes to retrospectively infer cell lineages in native contexts and to serve as genetic barcodes to measure clonal dynamics in complex cellular populations. Further, somatic mutations in mitochondrial DNA (mtDNA) are tracked by single cell genomic approaches for simultaneous analysis of single cell lineage and state. Applicants further show that mitochondrial mutations can be readily detected with contemporary single cell transcriptomic and epigenomic technologies to concomitantly capture gene expression profiles and chromatin accessibility, respectively.

Abstract: The present invention provides dihydropyridazinone compounds of general formula (I) in which R1, R2 and R3 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative diseases, as a sole agent or in combination with other active ingredients.

Abstract: The invention provides for systems, methods, and compositions for manipulation of sequences and/or activities of target sequences. Provided are vectors and vector systems, some of which encode one or more components of a CRISPR complex, as well as methods for the design and use of such vectors. Also provided are methods of directing CRISPR complex formation in eukaryotic cells and methods for selecting specific cells by introducing precise mutations utilizing the CRISPR/Cas system.

Abstract: This disclosure provides a method and compositions for substantially increasing the concentration of DNA in macrophages of a patient. By administering to a patient one or more agents which prevent the activity of deoxyribonucleases within lysosomes of macrophages, degradation of DNA phagocytosed by macrophages is temporarily blocked, permitting its accumulation. This strategy has the potential to enhance the detection of genetic biomarkers from cells typically phagocytosed by macrophages, such as tumor cells, and thus has applications for early or residual detection of cancer.

Abstract: The disclosure provides novel programmable targeting sequences and applications thereof. The targeting sequences can be engineered for binding to proteins, polypeptides, and other macromolecules.

Abstract: The disclosure provides adenosine deaminases that are capable of deaminating adenosine in DNA to treat Hutchin-son-Gilford progeria syndrome (HOPS). The disclosure also provides fusion proteins, guide RNAs and compositions comprising a Cas9 (e.g., a Cas9 nickase) domain and adenosine deaminases that deaminate adenosine in DNA, for example in a LNA gene. In some embodiments, adenosine deaminases provided herein are used to correct a C1824T mutation in LMNA. In some embodiments, the methods and compositions provided herein are used to treat Hutchinson-Gilford progeria syndrome (HGPS).