The General Hospital Corporation

Massachusetts Institute of Technology

The Broad Institute, Inc.

Vamsi K Mootha

Yuhua Ji

Warren M Zapol

Luca Zazzeron

Sunil A Sheth

Vishal Gohil

Isha Jain

Anupam Patgiri

Zenon Grabarek

Denis Titov

Valentin Cracan

Alexis André Jourdain

Xiaoyan Robert Bao

Roland Nilsson

Mohit Jain

A system includes an enclosed tent or chamber or a breathing apparatus, a hypoxia induction system and a device for measuring arterial oxygen saturation in a subject breathing air within the enclosed tent or chamber or from the breathing apparatus. The hypoxia induction system delivers oxygen-depleted air having between 5 to 20% Oto the enclosed tent or chamber or breathing apparatus. The system adjusts the oxygen content of the oxygen-depleted air being delivered to the enclosed tent or chamber or the breathing apparatus based upon the arterial oxygen saturation measured by the device such that oxygen saturation in the subject is maintained within a range of 50% to 90%.

Compositions and methods that promote hypoxia or the hypoxia response for treatment and prevention of mitochondrial dysfunction and oxidative stress disorders

Described are methods for enhancing exon skipping in a pre-mRNA of interest, comprising contacting the pre-mRNA with interfering oligonucleotides such as antisense, siRNA, and miRNA. The exon skipping methods are associated with methods of treating a variety of diseases and conditions, including cancer.

Methods of modulating SLC7A11 pre-mRNA transcripts for diseases and conditions associated with expression of SLC7A11

The invention encompasses water-forming NADH and NADPH oxidases and the use of these enzymes to treat mammalian diseases or conditions associated with an elevated NADH/NAD+ ratio or NADPH/NADP+ ratio. Such pathologies include disorders caused by one or more defects in the mitochondrial respiratory chain, glucose metabolism disorders, cancers associated with reductive stress, and aging. The invention also provides a research tool for investigating the effect of exogenous water-forming NADH or NADPH oxidases on the metabolism of a mammalian cell, such as a human cell, and for elucidating the role of respiratory chain proteins in mitochondrial disorders.

Protein prostheses for mitochondrial diseases or conditions

Compositions comprising (i) lactate oxidase (LOX) and Catalase (CAT), preferably in a 1:1 molar ratio; or (ii) a fusion polypeptide comprising both LOX and CAT, e.g., LOXCAT, and methods of use thereof for reducing blood lactate levels, increasing blood pyruvate levels, and/or decreasing blood lactate/pyruvate ratio in a subject.

Extracellular redox enzyme system to alleviate disease

Methods of promoting hypoxia or the hypoxia response for the treatment or prevention of mitochondrial dysfunction and oxidative stress disorders are described. Methods for screening for targets of mitochondrial dysfunction and oxidative stress disorders are also described.

Model systems have shown that shifting a cell's reliance from oxidative phosphorylation (OXPHOS) to glycolysis can protect against cell death. Exploiting the therapeutic potential of this strategy, however, has been limited by the lack of clinically safe agents that remodel energy metabolism. The present invention identifies non-toxic small molecules (e.g., drug-like compounds) that are capable of modulating oxidative metabolism. One identified compound comprises meclizine. As described herein, meclizine, and its enantiomer S-meclizine, redirects OXPHOS to glycolysis. Such compounds could be protective or therapeutic in degenerative disorders such as diabetes, Huntington's, Parkinson's, and Alzheimer's disease and/or ischemic disorders including, but not limited to, stroke, heart attack, or reperfusion injuries.

Growing community of inventors

Boston, MA, United States of America

Vamsi K Mootha