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Compositions and methods for treatment of mitochondrial diseases and for differentiation of cells to neurons

A technology of mitochondria and neurons, applied in biochemical equipment and methods, gene therapy, animal cells, etc., can solve problems such as slow efficiency

Inactive Publication Date: 2015-10-28
THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Such reprogramming steps can be slow and inefficient, requiring extensive time and in vivo manipulation

Method used

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  • Compositions and methods for treatment of mitochondrial diseases and for differentiation of cells to neurons
  • Compositions and methods for treatment of mitochondrial diseases and for differentiation of cells to neurons
  • Compositions and methods for treatment of mitochondrial diseases and for differentiation of cells to neurons

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Effect test

Embodiment 1

[0256] To identify a panel of factors that effectively induce iDN formation in aged human fibroblasts, thirty candidate genes associated with DN development or maintenance were screened using a validated method for subreservoir formation (Takahashi et al., Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861-872 (2007); Vierbuchen et al., Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463, 1035-1041 (2010)). A single factor reservoir was identified containing Lmx1b, Nurrl, c-Fos, and Ebf1, which produced iDN with about 30% efficiency ( Figure 1a -d). This 4-factor combination induces high endogenous MASH1 expression ( Figure 1g ). The expression of neuronal progenitor cell markers Sox2 and Otx2 could not be detected by RT-PCR during the induction process ( Figure 1e ), indicating that this reprogramming does not involve a stem cell-like intermediate state. Expression of TH, DAT, VMAT2, PSD-9...

Embodiment 2

[0260] Mitochondrial defects in the PINK1(G309D) patient iDN were examined because studies in Drosophila and mammals have implicated PINK1 in mitochondrial regulation (Clark, I.E. et al., Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441, 1162-1166 (2006); Park et al., Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441, 1157-1161 (2006); Yang et al., Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation Drosophila Pink1 is rescued by Parkin. Proc Natl Acad Sci U S A 103, 10793-10798 (2006); Yu et al., The PINK1 / Parkin pathway regulates mitochondrial dynamics and function in mammalian hippocampal and dopaminergic neurons. Hum Mol Genet 20, 3 2011)). Compared to control iDNs, patient iDNs exhibit abnormal distribution and morphology of mitochondria in neuronal processes as monitored with the mito-GFP reporter ( Figure 2a ). Patient iDN show...

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Abstract

Methods and compositions are provided for the treatment of a mitochondrial disease in an individual with the mitochondrial disease. Aspects of the methods include administering an inhibitor of a Pumilio-like protein and / or an inhibitor of a serine / arginine-rich family of pre-mRNA splicing factor (SR) protein to a subject. Also provided are methods, compositions, systems and kits for transdifferentiating target cells to neurons, which find use in producing neurons for the development of new therapies, for experimental evaluation, as a source of lineage- and cell- specific products, and the like, for example, for use in treating human disorders of the CNS.

Description

[0001] Cross References to Related Applications [0002] Pursuant to 35 U.S.C. §119(e), this application claims priority to the filing date of U.S. Provisional Patent Application Serial No. 61 / 747,138, filed December 28, 2012; the entire disclosure of that application is incorporated herein by reference middle. technical field [0003] Provided herein are compositions and methods for treating a mitochondrial disease in a subject. [0004] Also provided herein are compositions and methods for differentiating cells (eg, somatic cells) into neurons. Background technique [0005] Mitochondrial dysfunction can produce a number of debilitating mitochondrial diseases or conditions characterized by poor growth, loss of muscle coordination, muscle weakness, vision problems, hearing problems, learning disabilities, heart disease, liver disease, kidney disease, gastrointestinal disturbances, respiratory disorders , neurological problems, autonomic dysfunction, and / or dementia. In ma...

Claims

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Application Information

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IPC IPC(8): C12N5/00
CPCC12N5/0619A61K31/13A61K31/198A61K31/713A61K35/30A61K45/06C12N15/113C12N2310/14C12N2501/60C12N2501/998C12N2506/1307A61K31/7105C12N2320/30C12N2503/02A61K2300/00
Inventor 鹿炳伟斯蒂芬·格尔克
Owner THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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