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The invention relates to a plasmid that enables gene knowndown (via CRISPRi) in human induced pluripotent stem cells (iPSCs), including derived cell types such as neurons. The plasmid contains homology arms to direct insertion of a cassette into the CLYBL safe-harbor locus in the human genome. The cassette expresses CRISPRi machinery using a CAG promoter. The CRISPRi machinery consists of double degron-tagged dCas9-BFP-KRAB. Addition of the small molecule trimethoprim to cell culture media stabilizes the degron and thereby increases dCas9-BFPKRAB levels, enabling CRISPRi activity.

This invention includes the identification of a new mutation in the collagen type VI (COL6A1) gene, including a method for diagnosing and treating patients with this mutation. Collagen type VI-related dystrophies (COL6-RD) are devastating neuromuscular disorders that manifest with progressive generalized muscle weakness, contractures, and respiratory failure. Currently, no cure exists for COL6-RD.

The invention is a novel longer-lived mouse model for Gaucher disease. Gaucher disease is a genetic disorder that results from deficiencies in the enzyme glucocerebrosidase (GBA). The use of animal models to study how the disease progresses has been invaluable in research of this disorder. However, existing mouse models have been limited due to early mortality because the GBA enzyme plays an important role in lysosomal storage.

This technology includes microRNAs for use in cell lines for protein production and potentially future treatments of cancer or diseases related to metabolism. Mmu-miR-466h was identified as a major apoptotic regulator in suspension adapted Chinese Hamster Ovary cells. Mmu-miR-466h was found to have the pro-apoptotic activity by targeting some anti-apoptotic genes for degradation during the exposure of CHO-S cells to the nutrients depleted media.

This technology includes a compound for use as a selective agonist of the A1 adenosine receptor (AR) for therapeutic hypothermia and other conditions. We have examined various synthesized nucleosides in a model of mouse hypothermia, in conjunction with AR knockout mice, to characterize the biological profiles. In trying to identify novel highly selective A1AR agonists that have superior in vivo activities, we have adapted a means of rigidifying the ribose moiety of adenosine in the form of a bicyclic (N)-methanocarba ring.

This technology includes a method using ionophores to reduce sickling in patients with sickle cell disease. Sickle cell disease is caused by polymerization of a hemoglobin mutant, and the only approved treatment acts by replacing sickle hemoglobin with fetal hemoglobin, thereby increasing the delay time prior to polymerization. This drug is only partially successful because it does not induce fetal hemoglobin synthesis in all cells.

This technology includes compounds that are selective agonists of the A3 receptor for the treatment of various disorders such as cancer and autoinflammatory diseases. Structurally, these compounds extend the class of (N)-methanocarba derivatives that are selective agonists of the A3 receptor.

This technology includes a class of A3AR-selective agonists to be used therapeutically to treat a variety of conditions, including chronic pain, cancer, and inflammatory diseases. This class of compounds produced full agonists of the human A3AR of nanomolar affinity that were consistently highly selective (>1000-fold vs. A1AR and A2AAR). The selectivity at mouse A3 receptors is smaller, but the compounds are still effective in vivo in reducing or preventing development of neuropathic pain.

This technology includes three new chemical entities discovered for antibacterial and antifungal activities. The compounds are novel tetramic acid containing polyketides obtained from two different Amycolatopsis strains. Their planar structures and relative stereochemistry were elucidated by 1D and 2D NMR methods, including 1H-1H and 13C-13C COSY, TOCSY, HSQC, HMBC and ROESY. Whole genome sequencing of these two strains revealed a 158 kb biosynthetic gene cluster (BGC) containing a 23-module, mixed NRPS-PKS pathway responsible for their biosynthesis.

This technology includes a sphingosine kinase 1 (Sphk1) knockout mouse model for use in developmental biology research. Sphingosine-1-phosphate (S1P) is synthesized from sphingosine and ATP by the action of sphingosine kinase, and activates cell signaling. Two sphingosine kinases, SPHK1 and SPHK2, have been identified. To study the physiological function of SPHK1, Sphki null mice were generated. The mice were viable, fertile, with no obvious abnormalities. Total SPHK activity in most tissues was substantially reduced, suggesting the presence of other sphingosine kinases.