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This technology includes the combination therapy of tyrosine kinase inhibitors (TKIs) and tigecycline as a potential new treatment for acute myeloid leukemia (AML). The existing treatments available for AML are not adequate; for patients older than 60, the prognosis is poor, with a two-year survival probability of less than 10%. Tigecycline is a glycylcycline antibiotic that induces cell death via inhibition of mitochondrial protein synthesis.

The present invention is directed to a synthesis of a dual-target inhibitor of cannabinoid-1 (CB1R) receptor and inducible nitric oxide synthase, and more specifically, to an improved process for synthesis of (S,1E,NE)-N-(1-aminoethylidene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide.

This technology includes processes for the synthesis of VBP15 (17a,21-dihydroxy-16a-methyl-pregna-1,4,9(11)-triene-3,20-dione) of high purity and large quantities as a treatment for Duchenne muscular dystrophy. The synthesis of VBP15 has several deficiencies which has hindered larger-scale preparation for clinical evaluation and potential manufacturing. The deficiencies included formation of significant levels of undesired epoxide impurity, formation of undesired ketone impurity, and resultant need for costly chromatographic purification.

This technology includes the use of the Anneal-Pool-Ligate-Sequence method (APLS) to quantify the cellular expression of dozens of genes for high throughput chemical library screening. This method is performed by culturing eucaryotic cells in 384-well format microplates, treating the cells with a library of chemicals, and producing cell lysates. Oligodeoxynucleotide (oligo) pairs representing (21) selected genes, and carrying index sequences for each well (384) and microplate (26), are annealed to mRNAs in cell lysates.

This technology includes a group of 20 drugs that can be further developed as a treatment for chordoma. Chordoma is a rare, slow-growing malignant tumor arising from remnants of the fetal notochord, with a high recurrence rate and no effective chemotherapy agents. These 20 drugs inhibited chordoma cell growth, with potencies ranging from 10 to 370 nM in the chordoma cell line UCH1 cells. These agents also had significant inhibitory effects on chordoma patient cells, C24, C25, and C32.

This technology includes the compositions and methods for inhibiting PIN1 for the treatment of disorders characterized by elevated PIN1 levels (e.g., immune disorders, proliferative disorders, and neurodegenerative disorders) with small molecules. Pin1 dysregulation has been associated with a number of pathological conditions. In particular, PIN1 has been shown to promote oncogenesis by modulating several oncogenic signaling pathways and its overexpression has been shown to correlate with poor clinical outcome.

Monoclonal antibodies (mAbs) have become a mainstay of therapy for many cancers. However, antibody therapy is not completely effective in some applications due to loss of the target surface antigen on cancer cells. Such mAb-induced “escape variants” are no longer sensitive to the therapeutic mAb therapy. It was observed that the escape variants carried covalently bound complement activation fragments, especially C3d. NIH inventors have generated several C3d-specific mouse and rabbit monoclonal antibodies to re-target cells that have escaped from mAb therapy.

This technology includes a stable pharmaceutical formulation of propofol hemisuccinate for inhalation delivery to treat intractable epilepsy and migraine. The formulation can be used to treat a patient experiencing a seizure aura to prevent a motor seizure. Alternatively, the formulation can be used to treat an epileptic patient who is experiencing seizure clusters in an out-of-hospital or in-hospital setting. For migraines, the formulation can be used to treat a patient experiencing a migraine aura or early migraine to forestall the development of the full symptoms of a migraine headache.

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.

This technology includes a system that allows for robust differentiation of human-induced pluripotent stem cells (iPSC) into motor neurons within a time frame of 7 to 10 days. To differentiate the iPSC, a stable transgene is inserted into the CLYBL safe harbor locus in the human genome using TALENs. The transgene allows for doxycycline-inducible expression of the transcription factors (NGN2, ISL1, and LHX3) that are needed for the cells to differentiate to motor neurons. The technology is described in detail in the protocol paper published by Fernandopulle et al, cited below.