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Mitochondrial aldehyde dehydrogenase-2 modulators for protecting, expanding and increasing potency of hematopoietic stem cells

A technology of hematopoietic stem cells and hematopoietic cells is applied in the field of in vitro expansion of hematopoietic cells and improvement of hematopoietic cell efficacy, protection, expansion of hematopoietic cells and improvement of hematopoietic cell efficacy, and can solve the problem of less and sufficient expansion of HSC. Issues such as increasing HSC and HSC transplantation application restrictions

Inactive Publication Date: 2020-05-01
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

[0006] HSC transplantation applications have been somewhat limited to date due to the inability to expand HSCs sufficiently in vitro to make this approach feasible
Some patients will not receive treatment because there are too few HSCs available for transplantation

Method used

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  • Mitochondrial aldehyde dehydrogenase-2 modulators for protecting, expanding and increasing potency of hematopoietic stem cells
  • Mitochondrial aldehyde dehydrogenase-2 modulators for protecting, expanding and increasing potency of hematopoietic stem cells
  • Mitochondrial aldehyde dehydrogenase-2 modulators for protecting, expanding and increasing potency of hematopoietic stem cells

Examples

Experimental program
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Effect test

example

[0230] The following examples are presented to provide one of ordinary skill in the art with a complete disclosure and description of how to make and use the invention, and are not intended to limit the scope of what the inventors believe to be their invention, nor to represent that the following experiments were all or The only experiment. Efforts have been made to ensure accuracy with respect to numbers used (eg, amounts, temperature, etc.), but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric. Standard abbreviations can be used, for example, bp, base pair; kb, kilobase; pl, picoliter; s or sec, second; min, minute; h or hr, hour; aa, amino acid; kb, kilobase; bp, base pair; nt, nucleotide; i.m., intramuscular (ground); i.p., intraperitoneal (ground); s.c., subcutaneous (groun...

example 1

[0231] Example 1: Effect of increased aldehyde load on HSC interferon stress response.

[0232] DNA interstrand crosslinks (ICLs), normally repaired by the Fanconi anemia (FA) complex gene products, can be induced by reactive aldehydes (eg, acetaldehyde). A hypomorphic missense mutation of aldehyde dehydrogenase 2 (ALDH2) is found in about 560 million people worldwide, resulting in a reduced ability to metabolize acetaldehyde and other toxic aldehydes. The ALDH2*2 genotype causes the well-known disulfiram-like "Asian flushing syndrome" observed after ethanol intake, but also increases susceptibility to cancer, aplastic anemia, Higher risk and faster progression to bone marrow failure.

[0233] The effect of increased aldehyde load in HSCs caused by genetic variation (ALDH2*2) and environmental exposure (ethanol treatment (challenge) to increase aldehyde load) was investigated. Hematopoietic stem progenitor cells (HSPCs) from wild-type (WT) and ALDH2*2 / *2 mice between 6-30 we...

example 2

[0237] Example 2: ALDH2 activators protect and expand HSCs in vivo.

[0238] Mice (wild-type C57BL / 6N) were administered Alda-1 (10 mg / kg.day) or vehicle control (50% DMSO / 50% PEG-400) for 3 months by continuous infusion via a subcutaneous osmotic pump.

[0239]

[0240] HSC function was then analyzed in vehicle control and Alda-1 treated mice. Mice treated with Alda-1 exhibited marked HSC expansion. It was observed that mice treated with Alda-1 exhibited a 4-fold increase in (LT)-HSC ( Figure 1A ), and mice treated with Alda-1 exhibited a 2-fold increase in (ST)-HSC ( Figure 1B ). see Figure 1A and Figure 1B , error bars show standard deviation, significance calculated with Student's t-test. *=p≤0.05. In conclusion, chronic Alda-1 administration was well tolerated in vivo and resulted in the expansion of HSCs.

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Abstract

The present disclosure provides methods of protecting and expanding hematopoietic cells. The present disclosure also provides methods of increasing the potency of hematopoietic cells. Aspects of the methods include contacting a starting population of hematopoietic cells with a therapeutically effective amount of at least one ALDH2 agonist. Aspects include in vivo, in vitro and ex vivo methods of protecting, expanding and increasing the potency of hematopoietic cells. Aspects of the methods include treating an individual who is undergoing chemotherapy or radiation treatment for cancer, has beenexposed to damaging toxins, has a genetic disease that leads to HSC damage, bone marrow failure, an autoimmune disease, or development of hematologic malignancies. Aspects of the methods also includetreating a healthy individual who is a stem cell transplant donor.

Description

[0001] cross reference [0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 559,311, filed September 15, 2017, which is hereby incorporated by reference in its entirety. [0003] Statement Regarding Federally Funded Research [0004] This invention was made with government support under Grant No. AA011147 awarded by the National Institutes of Health. The government has certain rights in this invention. Background technique [0005] Hematopoiesis, the formation of blood cell components, consists of a developmental cascade in which hematopoietic stem cells (HSCs) generate lineage-committed cells and repeat the process of self-renewal. Hematopoietic stem cells are usually cells with dual abilities of self-renewal and multi-lineage differentiation. The main sources of HSC are bone marrow and umbilical cord blood. HSCs are used for transplantation applications. Bone marrow transplantation has been used in the treatment of various hematolog...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/422C07D413/14C07D413/12
CPCA61K31/36C12N2501/71C12N5/0647C12N15/102A61K48/005
Inventor K·温伯格L·D·范·瓦森霍夫D·莫克利-罗森C-H·陈
Owner THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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