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This invention includes human induced pluripotent stem cell (iPSC) lines that harbor a single copy dCas9-BFP-KRAB at the CLYBL safe harbor locus (mediating CRISPR inhibition of human gene expression) and/or a single copy of dox-inducible NGN2 at the AAVS1 locus (enabling the differentiation of the iPSCs into neurons). The CRISPR-mediated inhibition of human gene expression is maintained into the differentiated neurons, permitting functional studies of targeted genes in neurons.

The technology includes Pink1 knockout HeLa cells that were generated using CRISPR technology. Pink1 is the key master gene to trigger degradation of mitochondria, mitophagy, and is implicated in familial Parkinson Disease. Knocking out Pink1 allows us to study the roles of Pink1 in many aspects of mitophagy and to display Pink1-dependent or independent activity. To create the HeLa cells, two CRISPR gRNAs targeting exon 1 and exon 7 of the Pink1 genome were used for transfection with Cas9 and GFP-C1 reporter. Cells were sorted 2 days after transfection and plated out in 96-well plates.

This invention includes HeLa cells that are engineered to inducibly express a mutant form of ornithine decarboxylase that is targeted to the mitochondrial matrix and forms insoluble protein aggregates. The presence of unfolded proteins in the matrix causes the accumulation of the mitochondrial kinase PINK1 and the E3 ubiquitin ligase PARK2/Parkin. These proteins play a critical role in degrading the mitochondria where they are expressed, a process call mitophagy. Mutations in these two genes are associated with familial Parkinson disease.

This technology includes two new salt forms for (2R,6R)-hydroxynorketamine (2R,6R-HNK), which is the lead molecule being developed for treatment-resistant depression. Currently, 2R,6R-HNK is being developed as the HCl salt. The HCl salt is slightly hygroscopic at high RH. This is a potential liability, especially in an oral pill form. Recently the malonate and salicylate salt have been discovered and found to have excellent crystalline behavior while also not having the hygroscopic liability the HCl salt holds. This represents a clear advantage.

This technology includes the compounds, compositions, and methods for treating CNS disorders and cancer with an inhibitor of a p21-activated kinase (PAK). PAK activation is shown to play a key role in spine morphogenesis, and attenuation of PAK can reduce, prevent or reverse defects in spine morphogenesis leading to improvements in synaptic function, cognition, and/or behavior. This could be used to treat a wide variety of CNS disorders such as schizophrenia, Alzheimer’s, Parkinson’s Disease, depression, bipolar, and many others.

In the last decade, prescription opioid abuse and misuse has been a major contributor to mortality in the United States, resulting in a serious national public health crisis. Nearly 12 million Americans used prescription opioids nonmedically in 2018, with >67,000 people dying from an opioid overdose.

This technology includes a variety of structures that can effectively target the c-Abl myristate binding pocket with increased potency and brain permeability. C-Abl is a ubiquitous non-receptor tyrosine kinase involved in signal transduction. In addition to its classic function in leukemia pathogenesis, c-Abl kinase is also thought to play a role in neuronal health, whereby deregulation of c-Abl could be related to early neuronal dysfunction and cytoskeletal alterations.

This technology includes compounds, pharmaceutical compositions and methods of treating or preventing neurological or psychiatric disorders for which inhibiting KCNH2-3.1 containing potassium channels provides a therapeutic effect. Polymorphisms in the KCNH2 gene have been associated with altered cognitive function and schizophrenia. The KCNH2 gene encodes the protein which forms the human ether-a-go-go related (hERG) voltage-gated potassium channel 4, 5.

This technology includes a newly discovered molecule 2,6-Dimethoxy-4-(5-Phenyl-4-Thiophen-2-yl-1H-Imidazol-2-yl)-Phenol (DPTIP) as potent inhibitor of neutral sphingomyelinase 2 (nSMase2), to be used for the treatment of neurodegenerative and oncologic diseases. This discovery was identified through unbiased screening of the National Center for Advancing Chemical Sciences (NCATS) chemical library using our human neutral sphingomyelinase assay.

This technology includes a precise measurement assay of cellular FMRP levels in patients, which can assist in the diagnosis and assess the severity of Fragile X syndrome (FXS). FXS is an X-linked disorder that produces intellectual disability, cognitive impairment, epilepsy, depression and anxiety. FXS is caused by mutations in the Fragile X Mental Retardation-1 (FMR1) gene that result in the absence or a loss of function of its protein product, FMRP.