A novel method for selectively targeting and modulating brain border-associated myeloid cells for the treatment of neurological disorders.

This technology represents a pioneering approach to vaccine development, focusing on encapsulated adjuvants and antigens to enhance efficacy while minimizing side effects.

A revolutionary one-shot therapy for juvenile and adult-onset glaucoma affected by MYOC mutations, offering a permanent cure for this previously untreatable disease.

IS110 family transposons encode a protein component (also referred to as the transposase) and a non coding RNA component (also referred to as the bridgeRNA or bRNA). In its naturally occurring context, a bRNA-bound transposase directs the integration of its cognate transposon (also referred to as the donor) into target DNA sites. The nucleic acid sequence and structure of the bRNA partially determines the sequence identify of the terminal ends of the mobilized donor, and the sequence identify of the target DNA molecule (also referred to as the target or target DNA). UC Berkeley researchers have developed a programmable gene editing technology based on IS110 family transposons that can be used for targeted insertions, deletions, excisions, inversions, replacements, and capture of DNA in vitro and in vivo. Additionally, this technology can be multiplexed to achieve complex assembles of multiple fragments of DNA.

Efficient delivery and expression of exogenous proteins in cell populations (e.g., cells in the body) for gene therapy / gene editing applications, is an important goal in biomedicine. This can be hampered by inefficient transport of enzymes from outside the body to cells within the body. When delivering nucleic acids or proteins of interest (e.g., DNA editing enzymes), most delivery methods can only reach and enter a small subset of cells within a tissue. There is a need for compositions and methods for improved delivery of proteins of interest, and such is provided herein. UC Berkeley researchers have discovered that delivery of a molecular cargo to a target cell can be more efficiently achieved by using a cell as the delivery vehicle. This can be accomplished by delivering a nucleic acid encoding an enveloped delivery vehicle (EDV) (one that comprises a molecular cargo), to a producer cell where the producer cell produces the EDV and thereby delivers the molecular cargo to neighboring cells (referred to herein as receiver cells). Thus, there is no human intervention between delivery of a subject nucleic acid (encoding the EDV) and subsequent delivery of EDVs to target cells (receiver cells).  

A novel dendronized polypeptide architecture for efficient and safe mRNA delivery, suitable for anti-tumor immunotherapy.

SUMO inhibitors offer a promising new therapy for protecting against cardiac rhythm disturbances and pump failure associated with heart attacks.

Professor Giulia Palermo and colleagues from the University of California, Riverside and the University of Rochester have developed high-fidelity Cas13a variants with increased sensitivity for base pair mismatches.The activation of these Cas13a variants can be inhibited with a single mismatch between guide-RNA and target-RNA, a property that can be used for the detection of SNPs associated with diseases or specific genotypic sequences.  

Researchers from UC San Diego have engineered human zinc finger-containing fusion proteins that target and can destroy or modify human RNA transcripts that contain expanded G4C2 hexanucleotide repeats. This approach, which they have termed zinc fingerdirected RNA targeting, provides a means to, depending on the fusion protein, 1) target and degrade disease-causing RNA transcripts containing G4C2 expansions and to 2) target, label, and track the same transcripts in living cells.

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Programmable base editors are a class of genome editing effector proteins that can make precise, targeted changes to DNA base pairs in a narrow window of genomic sequence without reliance on double-stranded breaks in chromosomal DNA. Base editor proteins include a deaminase fused to a CRISPR-Cas effector protein (e.g., nCas9). Base editor proteins are challenging to produce in high yields via recombinant expression in E. coli. This has limited its clinical use to mRNA/gRNA delivery; this is in stark contrast to Cas9 nuclease, which has been used in multiple clinical trials in its protein-based RNP format. There is a need for base editor proteins that are highly active and can be produced with high yield. Such is provided by the compositions and methods described herein. UC Berkeley researchers have overcome the limitations associated with producing a CRISPR-Cas base editor by creating a CRISPR-Cas fusion protein with the deaminase fusion protein.  

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Reseachers from UC San Diego demonstrated a proof of principle for a CAGEX RNA-targeting CRISPR–Cas13d system as a potential allele-sensitive therapeutic approach for HD, a strategy with broad implications for the treatment of other neurodegenerative disorders.

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Optimizing the editing efficiency of CRISPR-mediated enzymes is still needed.  This is especially true in therapeutic use cases, when it would be ideal to attain high rates of editing via a low, transient dose of the enzyme in the ribonucleoprotein (RNP) format used for multiple ex vivo clinical trials. Because many CRISPR enzymes are of bacterial origin, fusion to NLS motifs can greatly enhance editing efficiency. However, CRISPR protein yields can decrease – sometimes dramatically – if the construct bears toomany NLSs. UC Berkeley researchers have developed CRISPR proteins with enhanced editing efficiencies by introducing multiple nuclear localization signal (NLS) fused at rationally selected sites within the backbone of CRISPR-Cas9. These Cas9 variants showed they can improve editing efficiency in T cells compared to constructs with terminally-fused NLS sequences and can be produced with high purity and yield.  

Class 2 CRISPR-Cas are streamlined versions in which a single Cas protein bound to RNA is responsible for binding to and cleavage of a targeted sequence. Theprogrammable nature of these minimal systems has facilitated their use as a versatile technology for genome editing.  CRISPR-Cas enzymes with reduced requirements for a protospacer-adjacent motif (PAM) sequence adjacent to the target site could improve the breadth of target sites available for genome editing.  UC Berkeley researchers have developed a novel PAM-loose 12a variants, nucleic acids encoding the variant Cas12a proteins and systems using these variants that make the Cas12a-based CRISPR technology much easier to design a DNA target for carrying out genome editing in human cells. 

TnpB protein has generated interest as a potential compact genome-editing tool, due to the short amino acid sequence (408 AAs for ISDra2 TnpB), which overlaps with the wRNA sequence in their genomes of origin. There is a need for compositions and methods that provide more efficient TnpB systems. UC Berkeley researchers have created variant TnpB proteins and variant wRNAs that increase cleavage activity and/or DNA binding activity (e.g., revealed as endonuclease activity such as on-target endonuclease activity). These variant TnpB proteins include an amino acid sequence having one or more amino acid substitutions relative to a corresponding wild type TnpB protein. Also provided are variant TnpB wRNAs that can form a complex with a TnpB protein and a second nucleotide sequence that can hybridize to a target sequence of a target nucleic acid, thereby guiding the complex to the target sequence.

The strategy employed by the invention is inspired by splicing factors, a category of RNA-binding protein that influence alternative splicing outcomes. These splicing factors are trans-acting, and act to enhance or silence exon inclusion by binding near or on the target exon and promoting or repressing the activity of splicing machinery. Scientifically, a highly programmable, minimally disruptive system to increase exon inclusion could allow for higher-throughput identification of functional roles of specific exons than have been previously shown.

Researchers at the University of California, Davis have developed a virally derived homolog to increase the inflammatory response desirable in cancer immunotherapy.

Researchers at the University of California, Davis have developed a viral peptide therapeutic that targets MYC-based cancerous tumors.

A primary reason behind the lack of progress in heart therapeutics is the inability to use phenotypic human tissue-level approaches to discover novel therapies. In recent years, there have been significant advances in the development microphysiological systems (MPS), which recapitulate organ-level and even organism-level functions.   MPS are quickly becoming representative of the future of disease modeling and drug screening, therefore paving the way for complex in vitro models to dominate the preclinical drug discovery landscape. However, there has yet to be an effective LNP formulation for therapeutic mRNA delivery to the heart. Therefore, despite progress in this area, one of the remaining challenges is to develop a LNP formulation capable of diffusing within human cardiac muscle, transfecting cardiomyocytes, and escaping the endo-lysosome before degradation more efficiently than current strategies. UC Berkeley researchers and others have developed compositions and methods using lipid nanoparticles for delivery of a payload (e.g., messenger RNA (mRNA)) to the heart, for delivery of mRNA for transfection of cells and methods of treatment.

Researchers at UC Irvine have identified and tested a molecular target that regulates T cell function during chronic viral infection and cancer. The molecular target is one of the high mobility group proteins (HMGB2). HMGB2 is a DNA binding protein that regulates transcriptional processes, meaning that its modulation will have profound effects on T cell differentiation and ultimate function by altering the expression of many genes.

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