Abstract: The present disclosure relates to synthetic oncolytic viruses comprising a lipid nanoparticle comprising one or more types of lipid and a self-amplifying replicon RNA comprising a sequence that encodes an immunomodulatory molecule.

Abstract: Provided herein are genetic circuits and encoded RNA transcripts that produce an output molecule in response to an RNA cleavage event that removes a degradation signal. In some embodiments, the genetic circuits described herein may be used for detecting RNA cleaver activities (e.g., in a cell). Methods of using the genetic circuits described herein in diagnostic or therapeutic applications are also provided.

Abstract: The present disclosure relates to synthetic oncolytic viruses comprising a lipid nanoparticle comprising one or more types of lipid and a self-amplifying replicon RNA comprising a sequence that encodes an immunomodulatory molecule.

Abstract: Provided herein are genetic circuits and cell state classifiers for detecting the microRNA profile of a cell. The cell state classifiers of the present disclosure utilize phosphorylation state of a transcription factor to control classifier output. Kinases and phosphatase pairs that function in phosphorylating or dephosphorylating the transcription factor are integrated into the circuit, their expression tuned by the presence of microRNAs of interest (e.g., in a cell). The genetic circuits and cell state classifiers may be used in various applications (e.g., therapeutic or diagnostic applications).

Abstract: The present disclosure, at least in part, relates to a miRNA based logic gate that comprises an engineered RNA carrier that comprises an nuclear export signal, a target site for a first miRNA and a pre-miRNA sequence for a second miRNA. Also provided by the disclosure are recombinant viruses (e.g., recombinant adeno-associated viruses (rAAV)) for delivery of the miRNA based logic gates.

Abstract: Provided herein are genetic circuits and cell state classifiers for detecting the microRNA profile of a cell. The cell state classifiers of the present disclosure are designed to incorporate multiple genetic circuits integrated together by transcriptional or translational control. Multiple inputs can be sensed simultaneously by coupling their detection to different portions of the genetic circuit such that the output molecule is produced only when the correct input profile of miRNAs is detected. The genetic circuits and cell state classifiers may be used in various applications (e.g., therapeutic or diagnostic applications).

Abstract: Disclosed herein are compositions comprising sterol-amino-phosphate compounds and methods of making and use thereof. Also disclosed herein are methods of making and methods of use of the compounds, compositions, and/or lipid particles disclosed herein. For example, the compounds and compositions are useful for treating a disease or disorder in humans and in animals. In some examples, the subject is a human male and the disease or disorder comprises male infertility.

Abstract: The disclosure provides methods for an in vitro evolution technique to identify and characterize mutations in the non-structural genes of an alphavirus replicon that increase the strength and persistence of expression of the replicon genome. Also provided herein are in vivo methods for administering to an animal model a mutated alphavirus replicon that codes for a gene of experimental or therapeutic interest in the subgenome of the alphavirus replicon. The mutations identified herein improve the therapeutic potential of self-replicating RNA, which may have implications for cancer immunotherapy and beyond, e.g., for vaccination or gene therapy.

Abstract: Provided herein are engineered HSV-1 vectors comprising a modified HSV-1 genome. The engineered HSV-1 vectors can be used to deliver genetic circuits (e.g., up to 100 kb) to cells in vitro or in vivo. Methods of treating or diagnosing a disease (e.g., cancer) using the engineered HSV-1 vectors described herein are also provided.

Abstract: The present disclosure is related to an engineered nucleic acid encoding a post-poly A signal RNA 3? to a terminator for expression of protein, and/or non-coding RNA. Also provided herein are methods for reducing epigenetic silencing, genetic modification, transcriptional regulation of the engineered nucleic acid described herein.

Abstract: Genetic circuits have been developed to regulate behaviors of replicon RNA in responses to small molecules, which has broader applications, such as for quantitative expression of cargo genes, temporary expression of immunomodulatory cytokines or antigens for better cancer immunotherapy or vaccination, and for increased safety in use of self-replicating vectors or in combination with other viral-delivery vectors. Described herein are genetic circuits suitable for systems that either require a tight off state or a slow off state, which can serve for instance where either a kill switch or prolonged protein expression (e.g., of vaccine antigens) are needed.

Abstract: Disclosed herein is a subgenomic promoter library derived from alphavirus. Also provided herein are methods of using the subgenomic promoters to produce antibodies and other molecules.

Abstract: The present disclosure provides systems and methods that train and use machine-learned models such as, for example, sequence-to-sequence models, to perform direct and text-free speech-to-speech translation. In particular, aspects of the present disclosure provide an attention-based sequence-to-sequence neural network which can directly translate speech from one language into speech in another language, without relying on an intermediate text representation.

Abstract: The present disclosure, at least in part, provides RNA cleavage based engineered bi-stable toggle switch utilizing the Programmable Endonucleolytic Scission-Induced Stability Tuning (PERSIST) platform. Also provided herein, are vectors encoding the engineered bi-stable toggle switch, and uses thereof.

Abstract: Disclosed herein are polynucleotides encoding multi-epitope polypeptides and assemblies thereof, and their use for treating or limiting Toxoplasma gondii infection.

Abstract: Compositions and methods are described for inducing an immune response against an immunogen in humans. The induced immune response is obtained by administering a heterologous prime-boost combination of an in vitro transcribed (IVT) self-replicating RNA (repRNA) and an adenovirus vector. The compositions and methods can be used to provide a protective immunity against a disease, such as a viral infection or a cancer, in humans.

Abstract: Provided herein are genetic circuits and encoded RNA transcripts that produce an output molecule in response to an RNA cleavage event that removes a degradation signal. In some embodiments, the genetic circuits described herein may be used for detecting RNA cleaver activities (e.g., in a cell). Methods of using the genetic circuits described herein in diagnostic or therapeutic applications are also provided.

Abstract: The present disclosure relates to synthetic oncolytic viruses comprising a lipid nanoparticle comprising one or more types of lipid and a self-amplifying replicon RNA comprising a sequence that encodes an immunomodulatory molecule.

Abstract: Provided herein are feedback controller circuits and cell state classifiers for tunable phosphorylation-based transcriptional regulation of gene expression in cells based on intracellular miRNA profiles and degradation by small molecules. Also provided are methods of using feedback controller circuits and cell state classifiers for determining the cell state, and methods of treating cells and subjects using feedback controller circuits and cell state classifiers encoding therapeutic output molecules.

Abstract: The present disclosure, at least in part, relates to an engineered RNA (e.g., microRNA and sgRNA), in the absence of an input signal, that is engineered to have a large enough energy gap between the formations of a first secondary structure, which is unrecognizable by an actuator, and a second secondary structure, which is recognizable by an actuator (e.g., Drosha and Cas protein).