Academia Sinica

National Health Research Institutes

Che-Kun James Shen

Yu-Chiau Shyu

Kuen-jer Tsai

Yu-Chi Chou

Tsann-Long Su

Weir-Torn Jiaang

Kuen-Jer Tsai

Lien-Szu Wu

Chun-Hao Hung

Chun-Chang Chen

Shih-Ling Huang

Provided herein are compounds of Formula (I). The compounds described herein are useful in treating a disease associated with the expression of endogenous embryonic/fetal globin (e.g., γ globin) in erythrocytes (e.g., treating β-thalassemia and/or sickle cell disease through at least the induction of the globin gene expression in erythrocytes), and/or anemia (β-thalassemia and/or sickle cell anemia). The compounds described herein are useful in treating, delaying, and/or preventing the adverse effects of β-thalassemia and/or sickle cell disease, inducing γ globin production, and/or inducing the expression of embryonic/fetal globin genes in a subject, cell, tissue, or biological sample. Also provided in the present disclosure are pharmaceutical compositions, kits, and methods of using the compounds for inducing γ globin production described herein and for treating any of the target diseases described herein.

Compounds for uses in pharmacological induction of HBF for treatment of sickle cell disease and ß-thalassemia

The invention relates to a genetically modified mouse comprising a heterozygous mutation of Tardbp (TDP-43) gene in that the Asn at amino acid 390 in TDP-43 is substituted with an amino acid that is different from Asn, wherein the genetically modified mouse exhibits Amyotrophic lateral sclerosis (ALS)-like phenotypes, TDP-43 proteinopathies and/or motor neuron degeneration. The invention also so relates to an isolated spinal cord motor neuron differentiated from an embryonic stem cell (ESC) that is obtained from an offspring of a genetically modified mouse according to the invention. Methods for identifying an agent alleviating and/or suppressing ALS-TDP pathogenesis are also disclosed.

TDP-43 knock-in mouse model of amyotrophic lateral sclerosis

The invention found that first, the feasibility of transfer of tumor resistance and other healthy longevity characters through transplantation of bone marrow mononuclear cells (BMMNC) or hematopoietic stem cells (HSC)/hematopoietic stem and progenitor cells (HSPC) consisting of genetically engineered EKLF gene encoding the hematopoietic transcription factor EKLF. Secondly, the present invention demonstrates expression of EKLF in the long-term hematopoietic stem cells (LT-HSC), and thus EKLF as a target of regulation of hematopoiesis.

Methods for enhancing lifespan and/or treating cellular proliferative disorders by transplantation

A genetically-modified non-human animal model of longevity and increased health span, which is associated with reduced tumorigenesis and tumor metastasis, as well as related methods for increasing longevity and health span, reducing tumorigenesis and tumor metastasis, and identifying active agents that confer increased longevity or health span, or reduced tumorigenesis or tumor metastasis.

Animal model of longevity and related methods for increasing longevity and inhibiting tumorigenesis

The present invention includes a genetically-modified non-human animal model of longevity and increased health span, which is associated with reduced tumorigenesis and tumor metastasis, as well as related methods for increasing longevity and health span, reducing tumorigenesis and tumor metastasis, and identifying active agents that confer increased longevity or health span, or reduced tumorigenesis or tumor metastasis.

A method for treating a progressive neurodegenerative disorder with bone marrow stem cells and a G-CSF receptor agonist.

Methods for rescuing learning and/or memory deficits caused by alzheimer's disease by G-CSF

Methods for identifying a test agent as a modulator of the active DNA demethylation activity of a DNA methyltransferase are disclosed. The method comprises: a) providing a methylated DNA; b) providing the DNA methyltransferase; c) allowing the methylated DNA to react with the DNA methyltransferase for a sufficient time to perform a demethylation reaction and generate a demethylated DNA product in the presence or absence of a test agent; d) analyzing the extent of demethylation; and d) comparing the extents of the demethylation in the presence and absence of the test agent, and thereby identify the test agent as a modulator of the DNA demethylation activity of the DNA methyltransferase.

DNA 5-methyl cytosine demethylation activity of vertebrate DNA methyltransferases

Compounds, pharmaceutical compositions, and methods for treating anemia (&#x3b2;-thalassemia anemia or sickle cell anemia.

Methods and compositions for treating &#x3b2;-thalassemia and sickle cell disease

Methods for rescuing learning, memory and/or motor function deficits associated with frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) are disclosed. The method comprises: a) administering to an animal having FTLD-U a therapeutically effective amount of an autophagy inducer; b) causing a decrease in the amount of ubiquitinated TDP-43 aggregation forms in the brain of the animal; and c) causing an improvement of the learning, memory capacities and/or motor function of the animal.

Methods for treating frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U)

The present invention provides compounds (such as compounds of formula I-a) that induce &#x3b3; globin expression and pharmaceutical compositions thereof. Such compounds may have beneficial therapeutic effects. Compounds and compositions described herein may be used to treat hemoglobinopathies such as &#x3b2;-thalassemia and sickle cell anemia. 

A non-human animal model for amyotrophic lateral sclerosis (ALS) is disclosed. The animal model comprises a rodent whose spinal cord motor neurons have a loss of TAR-DNA binding protein-43 (TDP-43) function and phenotypes exhibit ALS-like symptoms. A method for identifying a candidate agent for treating, preventing and/or inhibiting ALS associated with a loss-of-function of TDP-43 is also disclosed.

Non-human animal model for amyotrophic lateral sclerosis (ALS) with loss-of-TDP-43 function

Non-human animal models for frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) are disclosed. The invention relates to a transgenic mouse whose genome comprises a transgene operably linked to a neuronal specific promoter effective for an increased expression of the transgene in the brain of the mouse, in which the transgene comprises a nucleotide sequence encoding TAR DNA-binding protein 43 (TDP-43). The transgenic mouse exhibits reduced or impaired learning and memory capacity, and may further exhibits progressively impaired or reduced motor functions. Methods of using such animal models are also disclosed.

Non-human animal model for frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U)

The invention relates to a transgenic animal whose somatic and germ line genomic DNA includes at least one copy of a transgene having (1) a transcriptional start site; (2) a promoter operably linked to the transcriptional start site; and (3) an enhancer operably linked to the promoter, the enhancer including the nucleotide sequence of SEQ ID NO:1, where the transgenic animal expresses a transcript driven by the promoter, the level of expression in at least one cell type of the animal being positively correlated with the copy number of the transgene.

Growing community of inventors

Taipei, Taiwan

Che-Kun James Shen