The present invention relates to a production method of a systemic sclerosis disease model using keratinocytes and fibroblasts differentiated from induced pluripotent stem cells derived from patients with systemic sclerosis, a systemic sclerosis disease model produced thereby, and a method for screening a therapeutic agent for systemic sclerosis using the same.

The systemic sclerosis disease model produced by the above production method can be effectively used for preventing or treating systemic sclerosis.

Targeted Factor VIII molecules comprising a Factor VIII linked with at least one domain that specifically binds to a membrane protein on a red blood cell is provided. The disclosed targeted coagulation factors prolong their duration of action and thus, are an improvement for the treatment of hematological diseases such as hemophilia A.

The present invention provides a mouse with liver damage, having a high degree of damage against the mouse's original hepatocytes while having a uPA gene in a heterozygous form, and a method for efficiently preparing the mouse. Specifically, the method for preparing a mouse with liver damage having the uPA gene in a heterozygous form comprises the following steps of: (i) transforming mouse ES cells with a DNA fragment containing a liver-specific promoter/enhancer and cDNA that encodes a urokinase-type plasminogen activator operably linked under the control thereof; (ii) injecting the transformed mouse ES cells obtained in step (i) into a host embryo; (iii) transplanting the host embryo obtained in step (ii) via the injection of the ES cells into the uterus of a surrogate mother mouse, so as to obtain a chimeric mouse; and (iv) crossing the chimeric mice obtained in step (iii), so as to obtain a transgenic mouse in which the DNA fragment is introduced in a heterozygous form.

The disclosure provides materials and methods useful in forming at least one bile duct or treating cholestatic disease or injury by transdifferentiating hepatocytes to cholangiocytes by delivery of an effective amount of an expressible Transforming Growth Factor β Type I Receptor (TGFBR1), Transforming Growth Factor β Type II Receptor (TGFBR2), SMAD3, SMAD1, SMAD2, SMAD5 or SMAD8/9, in either in vivo or in vitro environments. Another aspect provides a method of forming at least one bile duct or treating a cholestatic disease or injury by delivering an effective amount of JAG1, JAG2, DLL1, DLL3, DLL4, NOTCH1, NOTCH2, NOTCH3, NOTCH4 or the respective NOTCH intracellular domains either in vivo or in vitro. Also provided are methods for correcting mutant alleles of genes in the TGFβ and/or Notch pathways, e.g., JAG1 or NOTCH2, using ZFNs, TALENs, CRISPR or any other genome editing technique. Additionally, methods are provided for inducing increased expression of a normal, or wild-type, allele of a TGFβ or Notch pathway gene such as TGFBR1 or JAG1 using CRISPRa technology. Yet another aspect is drawn to a method of forming at least one bile duct or treating a cholestatic disease or injury by delivering an effective amount of a wild-type hepatocyte or a hepatocyte that has not been engineered to overexpress a gene product.

This invention provides a non-human vertebrate exhibiting a higher human liver cell growth rate, a higher human liver cell replacement rate, and higher histological-physiological human reproducibility than existing non-human vertebrates comprising the human liver transplanted therein and a method for producing such non-human vertebrate. Specifically, the method for producing a transgenic non-human vertebrate comprising human liver cells transplanted therein comprises transplanting human liver cells in a non-human vertebrate that has impaired or lowered immune reactions against humans in the presence of human IL-6 in vivo.

This invention provides compositions of active highly phosphorylated lysosomal sulfatase enzymes, their pharmaceutical compositions, methods of producing and purifying such lysosomal sulfatase enzymes and compositions and their use in the diagnosis, prophylaxis, or treatment of diseases and conditions, including particularly lysosomal storage diseases that are caused by, or associated with, a deficiency in the lysosomal sulfatase enzyme.

The present invention provides a model animal for establishing an effective therapy for a protein aggregation disease typified by Alzheimer's disease and the like.

More specifically, the present invention provides the followings: (A) a non-human animal that exhibits a degenerative symptom attributed to protein aggregation, wherein the degenerative symptom attributed to protein aggregation is induced by misfolding of the protein and said degenerative symptom is promoted; and (B) a method for producing the non-human animal that exhibits the degenerative symptom attributed to the protein aggregation, comprising the following (1) and (2): (1) inducing misfolding of the protein to cause the degenerative symptom attributed to the protein aggregation in the non-human animal, and (2) giving a treatment to promote the degenerative symptom attributed to the protein aggregation in the non-human animal.

The present invention provides compositions for use in recovering and/or ameliorating deterioration of physiological functions due to aging. Provided are: a cell overexpressing GDF6 protein or an miR-17 family member; a composition for use in treating a senescence-related condition, containing GDF6 protein; a composition for use in treating a senescence-related condition, containing a human expression vector for GDF6 protein or an miR-17 family member; and a composition for use in treating a senescence-related condition, containing a cell secreting GDF6 protein.

Provided is a nonhuman animal model that is obtained by modifying a gene encoding thioredoxin and useful as a disease model of aging, kidney diseases, cardiovascular diseases, hypertension, aortic dissection, chronic obstructive lung disease, age-dependent epilepsy, abnormality of lipid metabolism, anemia, osteoporosis, abnormal immunity, etc. These variety of phenotypes are caused by the fact that a modification of a gene encoding thioredoxin induces hypofunction of thioredoxin expressed in multiple organs throughout the body. The gene encoding thioredoxin is a gene selected from among TXN, TRX, TRX1, RRDX, Txn1, Txn, Trx1 and ADF.

The purpose of the present invention is to provide a molecule having a significant effect on the development of fibrosis and a substance capable of inhibiting fibrosis. This biomarker for fibrosis comprises RNA binding motif protein 7 (RBM7) and is useful as a biomarker for diagnosis of fibrosis. This fibrosis detection method comprising the step of detecting RBM7 in a biological sample from a subject preferably using an anti-RBM7 antibody is useful for diagnosis of fibrosis. This antifibrotic agent containing a substance which inhibits the expression of RBM7, preferably at least one nucleic acid drug selected from the group consisting of siRNAs, shRNAs, dsRNAs, miRNAs, and antisense nucleic acids against RBM7, is useful for treatment of fibrosis.