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(SD2021-089) Unbiased approach for identification of regulators of materials and molecular uptake into cells

A major bottleneck in nanocarrier and macromolecule development for therapeutic delivery is our limited understanding of the processes involved in their uptake into target cells. This includes their active interactions with membrane transporters that co-ordinate cellular uptake and processing. Current strategies to elucidate the mechanism of uptake, such as painstaking manipulation of individual effectors with pharmacological inhibitors or specific genetic knockdowns, are limited in scope and biased towards previously studied pathways or the intuition of the investigators. Furthermore, each of these approaches present significant off-target effects, clouding the outcomes. Methods for intracellular transport of nucleic acids are much sought after in the context of both in vitro delivery reagents and in vivo therapeutics. Recently, we found that micellar assemblies of hundreds of amphiphiles consisting of single-stranded DNA which has been covalently linked to a hydrophobic polymer, referred to as DNA-polymer amphiphile nanoparticles or DPANPs, can readily access the cytosol of cells where they modulate mRNA expression of target genomes without transfection or other helper reagents, making them potential therapeutic nucleic acid carriers. However, despite their effective uptake properties and efficacy in the cytosol, it was unknown how these polyanionic structures can enter cells. Indeed, generally, bottlenecks in understanding and achieving delivery and uptake remain a forefront issue in translatability of macromolecular and nanomaterials-based therapeutics generally, including with respect to nucleic acid therapies. The nature of pooled screening requires amplifying a single ~200nt region per cell, leading to screens that require amplification from tens-to hundreds of micrograms of genomic DNA. Inhibitory effects of high DNA concentration per PCR have led to a variety of solutions, ranging from simply pooling hundreds of PCR reactions to utilizing restriction enzyme sites present in the lentiviral backbone constant regions flanking the sgRNA to perform DNA gel electrophoresis and size selection to remove undesired gDNA. However, these approaches can be both expensive and have significant handling challenges when scaled to large screens.

Compositions and Methods for Treating Viral Infections

Researchers at the University of California, Davis (“UC Davis”) have developed methods for screening and targeting regions of viral genomes to identify drugs that inhibit the replication of RNA viruses.

Sequential Targeting and Crosslinking Nanoparticles for Tackling the Multiple Barriers to Treat Brain Tumors

Researchers at the University of California, Davis have developed an approach to improve drug delivery to tumors and metastases in the brain. Their multi-barrier tackling delivery strategy has worked to efficiently impact brain tumor management while also achieving increased survival times in anti-cancer efficacy.

Methods Related To Cell-Microgel Encapsulation In Injectable Formulations

Injectable hydrogels are attracting increasing interest for the therapeutic delivery of cells to tissue. However, these hydrogel formulations can suffer from engraftment efficiencies of less than 5% when delivered to native tissue. These poor engraftment efficiency rates are often attributed to high shear stresses during delivery and inability to provide a stable three-dimensional niche at the delivery site. The inventors have developed a technique for encapsulating cells in the pore space between microscopic hydrogel particles by employing the yield stress fluid properties of packs of microgels. The technology protects the cells from mechanical stress during delivery and facilitates integration to the native tissue. During delivery, the packs of microgels undergo plug flow in which the pressure drop across the length of the pipe is compensated solely by frictional forces at the interface between the pipe wall and microgels. At the delivery site, the pack of microgels behave as an elastic solid across the range of physiological frequencies and provide a stable 3D culture paradigm to support engraftment.Furthermore, the inventors address the challenges associated with cryopreserving, transporting, and delivering this injectable formulation from benchtop-to-bedside with a concept for a perfusable delivery device. The device encapsulates cells in the pore space of the microgels and confines the formulation to a fixed volume where researchers can perfuse liquid freeze/thaw or maintenance media, differentiation factors, and anti-inflammatory agents at virtually any time prior to delivery to the tissue. The porous microgel network facilitates this process and makes the formulation amenable to transport and storage which would otherwise be unattainable in hydrogel formulations.

Slow Ion/Salt-Releasing Biodegradable Hydrogel for Aqueous Applications

This invention is a biodegradable hydrogel mixed with minerals/chemical substances to slowly release ions/salts into the nearby aqueous waterbody through gradual abrasion of surface gel layers performed by underwater current.

Genetically Engineered Dendritic Cell-Derived Vaccines

Researchers at the University of California, Irvine have developed a new vaccine which generates a targeted, specific immune response with fewer complications than currently available vaccines.

Transformable Smart Peptides as Cancer Therapeutics

Researchers at the University of California, Davis have developed smart, supramolecular, materials that can assemble into nanoparticles. These particles can then be used to target tumor cells.

Viral Capsid Mutants with Dramatically Enhanced Cancer Cell Uptake

The inventors have identified two double mutant capsids with positively charged surfaces for improved delivery of small molecule- and nucleic acid-based therapeutics. Fitness landscape engineering of bacteriophage MS2 virus-like particles (VLPs) was used as a guide for the discovery. The engineered capsid variants have internalization efficiencies as much as 67-times higher than wild-type MS2 VLPs. Internalization of these cationic variants depends on interactions with cell surface sulfated proteoglycans. They are bio-physically similar to wild-type MS2 with low cytotoxicity. The best-performing cationic MS2 capsids can deliver a potent anticancer small molecule therapeutic with efficacy levels similar to antibody-drug conjugates.  

Minimally Invasive Percutaneous Delivery System for a Whole-Heart Assist Device

Researchers at UCI have developed a minimally invasive mechanism to help deliver and implant a cardiac assist device inside the body to help patients with heart failure.

(SD2020-497) Light-activated tetrazines enable live-cell spatiotemporal control of bioorthogonal reactions

Bioorthogonal ligations encompass coupling chemistries that have considerable utility in living systems. Among the numerous bioorthogonal chemistries described to date, cycloaddition reactions between tetrazines and strained dienophiles are widely used in proteome, lipid, and glycan labeling due to their extremely rapid kinetics. In addition, a variety of functional groups can be released after the cycloaddition reaction, and drug delivery triggered by in vivo tetrazine ligation is in human phase I clinical trials. While applications of tetrazine ligations are growing in academia and industry, it has so far not been possible to control this chemistry to achieve the high degrees of spatial and temporal precision necessary for modifying mammalian cells with single-cell resolution.

Multiplex Epigenetic Editing using a Split-dCas9 System

Researchers at the University of California, Davis have developed a new epigenetic editing system that overcomes packaging limitations of viral delivery systems and can be used for multiplexed epigenetic editing of a genome.

2-D Polymer-Based Device for Serial X-Ray Crystallography

Researchers at the University of California, Davis have developed a single-use chip for the identification of protein crystals using X-ray based instruments.

Peptides for Macromolecular Delivery

This invention includes: 1) Applying amphiphilic peptides (AP) (e.g. E5-TAT, INF7-TAT, or similar peptides) in novel scenarios for delivering CRISPR-Cas9 RNPs and performing genome editing in primary human cells of substantial clinical value (human pluripotent stem cells [HSPCs], T cells) and mouse neuronal progenitor cells in vitro or in vivo. These peptides have also been used for delivering plasmid DNA as a DNA vaccine into human cells in culture, and into mouse tissue in vivo to produce a robust immune response.  2) Novel peptide sequences (derivatives of E5-TAT or INF7-TAT) with improved properties and/or improved activity (relative to the founder peptides) in delivering cargo into target cells. The inventors have created a library of related sequences, all with distinct activity in delivering cargo to different cell types. These novel peptide sequences have been applied to the same scenarios as above, with improved outcomes compared to the parent peptides, E5-TAT or INF7-TAT, in genome editing, and may provide benefits in delivery of plasmid DNA as well. This is especially valuable when delivering to cell types that are notoriously difficult to transduce, such as HSPCs and T cells, leading to new therapeutic opportunities. Background Biological macromolecules offer great potential as therapeutics but the greatest hurdle that remains is their efficient cell entry into target cell types. Cell entry is limiting for two very promising technologies, DNA vaccines and genome editing, and this invention aims to address the unmet need. DNA vaccines would provide a rapid and inexpensive approach to vaccination for a wide range of viral pathogens, but have been hampered by poor delivery of the DNA into the target cells, resulting in an immune response not potent enough for effective vaccination. DNA vaccines involve delivering a plasmid which encodes a viral protein into the nucleus of human cells, where it can be transcribed and then expressed to be recognized by the immune system. In order to improve their efficacy, DNA vaccines have been delivered via in vivo electroporation, a painful process that requires specialized equipment and repeat dosing. Genome editing holds immense therapeutic promise for correcting the genetic mutations underlying disease, or for preventing or treating non-genetic disease. Delivery of the genome editing enzymes, such as CRISPR-Cas9, into the cytosol or nuclei of cells in need of manipulation remains the largest hurdle. Delivering CRISPR-Cas9 as a ribonucleoprotein (RNP) complex offers many advantages compared to other approaches (e.g. the use of viral vectors or lipid nanoparticles), but the RNP lacks an inherent method of cell entry. Amphiphilic peptides (AP) enable transduction of macromolecules into cells and therefore the inventors have aimed to apply APs to delivering cargo such as CRISPR-Cas9 RNPs as well as plasmid DNA into target cell types. The activity of a specific AP in delivering cargo into a the cytosol of a cell is often dependent on the specific cargo being delivered as well as the specific cell type. Therefore, the inventors have created libraries of related APs with diversity in their amino acid sequence in order to allow delivery of macromolecular cargo to a range of cell types, dependent on the specific application. A peptide sequence derived from influenza hemagluttinin sequence, HA2, has been previously described and applied as an endosomolytic peptide (ELP). When the HA2 sequence is appended with TAT, a positively charged cell penetrating peptide sequence derived from the HIV TAT protein, the fusion peptide “HA2-TAT” is able to deliver macromolecular cargo across the cell membrane and also act as an ELP to allow endosomal escape. Derivatives of the HA2-TAT sequence with changes in the amino acid sequence of the peptide, such as the peptide “E5-TAT,” has improved properties compared to HA2-TAT in solubility as well as delivering cargo into cells. The INF7-TAT peptide has similar properties, where INF7 is another glutamine-rich analog of HA2 with improved properties for endosomal escape. HA2 and its derivates (E5, INF7) with and without fusion to cell penetrating peptides (HA2-TAT, E5-TAT, INF7-TAT) have been applied to delivering macromolecular cargo such as proteins and nucleic acids into cells.

Digital Droplet Infusion System for High-Precision, Low-Volume, Delivery of Drugs or Nutritional Supplements

Researchers at the University of California, Davis have developed the first, digital, droplet infusion system capable of high-precision delivery of very low-volume therapeutics or nutraceuticals.

Treatment Of Inherited Retinal Disease

Researchers at UCI have developed a method of treating inherited retinal diseases, such as Leber congenital amaurosis (LCA) and retinitis pigmentosa, by gene therapy of the RPE65 nonsense mutation. This method uses base editor-mediated genome-editing by viral delivery and lead to improved patient treatment through enhanced editing of single base pairs and reduced off-target genomic editing.

Electric Ratchet Based Ion Pumps

UCI researchers developed a new device that uses electricity to drive ion separation across a membrane. This device can increase the energy efficiency of various applications such as artificial photosynthesis, water desalination, and chemical separations.

Percutaneous Heart Valve Delivery System Enabling Implanted Prosthetic Valve Fracture

UCI researchers developed a percutaneous heart valve delivery system to deliver and implant a prosthetic valve. This system incorporates the means to fracture a previously implanted prosthetic valve in situ without interfering with the transcatheter valve to be implanted.

Intranasal Delivery of Oligonucleotides for Neurodegenerative Diseases

Delivery of oligonucleotide therapy to the central nervous system remains challenging. Neurodegenerative diseases, such as Huntington’s disease and Spinal Muscular Atrophy, can require intrusive and regular treatments, therefore a non-invasive delivery system would be very beneficial to patients. UC Irvine researchers have proposed a new method of therapeutic delivery utilizing a SARS-CoV-2 pseudovirus. Delivered intranasally, this system has the ability to bypass the blood brain barrier, making it an exciting approach to decrease risk for patients and ease the treatment process.

Novel Tunable Hydrogel for Biomedical Applications

Prof. Huinan Liu’s lab at the University of California, Riverside has developed a novel tunable hydrogel that achieves tunable crosslinking, reversible phase transition, and may be used as a 3DP scaffold. This new hydrogel utilizes dynamic coordination of its innate carboxylic groups and metal ions. Adding methylacrylate or other functional groups is not required for this technology and the resulting hydrogel is less toxic. Since the functionalization of this hydrogel is not required, it is less process-intensive and results in a more cost-effective hydrogel.  In addition, the UV curing is no longer needed since methylacrylate is no longer utilized to crosslink the hydrogel.   Fig 1: Optical micrographs of top view and cross-section of HyA hydrogels printed using cold-stage method and direct writing method. Hydrogels printed using direct writing method showed better structural integrity and stability.

Hemoglobin Carrying PEG Microspheres As Artificial Red Blood Cells

Researchers at the University of California, Irvine have developed artificial red blood cells consisting of hemoglobin that is tethered to polyethylene glycol (PEG) molecules and formed into microspheres.

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