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This technology relates to the description and therapeutic use of a small molecule that selectively binds to and activates the D3 dopamine receptor. Dopamine receptors (DARs) are members of the G protein-coupled receptor (GPCR) superfamily that play a critical role in cell signaling processes, especially modulating the transfer of information within the nervous system. Members of the DAR subfamilies share high sequence homology, especially the D2 and D3 DARs. Most currently available dopaminergic drugs cross-react with both subtypes to varying degrees.

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.

This technology includes the design and use of several nanobodies that bind to the SARS-CoV2 spike protein receptor binding domain and block spike protein interaction with the angiotensin converting enzyme 2 (ACE2) receptor. Nanobodies are 12-15 kDa single-domain antibody fragments that are more stable and easier to produce in large quantities compared to conventional antibodies. SARS-CoV2 is the virus responsible for the COVID19 pandemic. The SARS-CoV2 spike protein is responsible for viral entry into human cells via interaction with ACE2 on the cell surface.

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 the identification and use of antisense oligonuclecotides (ASOs) complimentary to the 5’UTR of SMN2 (Survival of motor neuron 2) for the treatment of spinal muscular atrophy (SMA). SMA is an autosomal-recessive motor neuron disease caused by the loss of both copies of the SMN1 gene. Copies of the similar gene SMN2 decrease the severity of this disease in a dose-dependent manner. Thus, increasing expression levels of the SMN2 transcript can be used to treat SMA.

3D spheroids have emerged as powerful drug discovery tools given their high-throughput screening (HTS) compatibility. The present invention presents a method for generating functional neural spheroids with differentiated human induced pluripotent stem cell (hiPSC)-derived neurons and astrocytes at cell type compositions mimicking specific regions of the human brain.

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.