US-12622898-B2 - Methods and compositions for improving bone marrow hematopoietic functions

Abstract

The present application provides methods and compositions for treating diseases or disorders related to hematopoietic dysfunctions and/or injuries, or for rejuvenating HSPCs.

Inventors

• Meng Zhao

Assignees

• SUN YAT-SEN UNIVERSITY

Dates

Publication Date

20260512

Application Date

20201016

Priority Date

20191018

Claims (8)

1. 1 . A method for rejuvenating an aged HSPC, comprising: attenuating an expression and/or function of Sphk2 of said aged HSPC; and/or enhancing an expression and/or function of Pdk3 of said aged HSPC.
2. 2 . The method of claim 1 , wherein said aged HSPC is obtained from an aged subject.
3. 3 . The method of claim 1 , wherein said expression and/or function of said Sphk2 is attenuated by inhibiting an expression and/or function of the Sphk2 gene, and/or inhibiting an expression and/or function of the Sphk2 protein.
4. 4 . The method of claim 1 , wherein said expression and/or function of said Sphk2 is attenuated with a Sphk2 inhibitor.
5. 5 . The method of claim 4 , wherein said Sphk2 inhibitor comprises a compound of formula (I) or a pharmaceutically salt thereof:
6. 6 . The method of claim 4 , wherein said SphK2 inhibitor comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof: wherein: R 1 s phenyl, or a phenyl substituted with a halogen; R 2 is aryl, heteroaryl, or a substituted aryl or heteroaryl; R 4 is H or alkyl; and n is an integer of at least 1.
7. 7 . The method of claim 2 , wherein said subject has been subjected to chemotherapy.
8. 8 . The method of claim 2 , wherein said subject has been subjected to bone marrow transplantation.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a National Stage Application and claims priority under 35 U.S.C. § 371 to Patent Cooperation Treaty application PCT/CN2020/121570, filed Oct. 16, 2020, which claims the benefit of Patent Cooperation Treaty application PCT/CN2019/112050 filed Oct. 18, 2019. Priority is claimed to these applications and the disclosure of these prior applications is considered part of the disclosure of this application and to the extent allowed the entire contents of the aforementioned applications are incorporated herein. SEQUENCE LISTING This application incorporates by reference in its entirety the Sequence Listing entitled “2022-04-15_262790-509361_ST25”, is 528 bytes in size and was created on Apr. 15, 2022, and filed electronically herewith. FIELD OF THE INVENTION The present application relates to methods and compositions for improving the functions of hematopoietic system, such as methods and compositions for enhancing and/or rejuvenating the hematopoietic functions. BACKGROUND Hematopoietic stem and progenitor cells (HSPC) are a group of primitive hematopoietic cells existing in hematopoietic tissues, and mainly serve to differentiate to produce various blood cells, such as red blood cells, platelets and white blood cells, to support the renewal of hematopoietic and immune systems of the body. HSPCs play an important role in the maintenance and post-injury repair of normal hematopoietic function of the body. Primary lesions, radiation from the environment, and chemical drugs and radiation in clinical treatment can all cause serious injuries to hematopoietic stem and progenitor cells, resulting in hematopoiesis dysfunction, poor hemogram index, white blood cell decrease, immune dysfunction, and even survival rate reduction in the patients. Therefore, to expand hematopoietic stem cell number and/or improve the hematopoietic function of hematopoietic stem cells is crucial to the treatment of hematopoiesis dysfunction and related diseases. Improving the hematopoietic stem cell number and function is also critical for accelerating hematopoiesis reconstitution for patient subjected to bone marrow transplantation. Further, during the process of aging, HSPCs gradually lose their self-renewal and regenerative potential, whereas the occurrence of cellular derailment strongly increases. Aged HSPCs may also be more susceptible to malignant transformation, leading to various disease and disorders. Aged HSCs also have reduced capacity to generate lymphocytes, which leads to comprised immune capacity during aging. However, currently, there are very limited therapeutic interventions that are effective in expanding hematopoietic stem cell number and/or improving their functions. There are also very limited interventions that might be useful in preventing or delaying the HSPC aging process, let alone reversing the HSPC aging process or rejuvenating aged HSPCs. SUMMARY The present application relates to methods, systems and compositions for preventing, treating and/or alleviating diseases or disorders of the hematopoietic system, such as those related to hematopoietic dysfunctions and hematopoietic injury. The present application also provides methods, systems and compositions for improving the hematopoietic function of hematopoietic stem cells, for promoting hematopoietic recovery after bone marrow transplantation, and/or for rejuvenating hematopoietic stem and progenitor cells. The method, system and composition of the present application may involve attenuating an expression and/or function of Sphk2, and/or enhancing an expression and/or function of Pdk3. Further, the present application relates to methods and systems for screening candidate agents for treating diseases or disorders related to hematopoietic dysfunction and/or hematopoietic stem cell injury, and/or for rejuvenating aged hematopoietic stem and progenitor cells. Such methods and systems may involve evaluating an effect of the candidate agent in attenuating an expression and/or function of Sphk2, and/or in enhancing an expression and/or function of Pdk3. In one aspect, the present application provides a method for preventing, treating and/or alleviating a disease or disorder related to hematopoietic dysfunction and/or hematopoietic injury in a subject in need thereof. In some embodiments, the method comprises attenuating an expression and/or function of Sphk2 in the subject. In some embodiments, the method comprises attenuating an expression and/or function of Sphk2 in a hematopoietic stem cell and/or progenitor cell (HSPC) in the subject. In some embodiments, the method comprises administering to the subject an HSPC, wherein an expression and/or function of Sphk2 of the HSPC is attenuated. In some embodiments, the method comprises administering to the subject an HSPC derived from a donor, wherein the donor has attenuated expression and/or function of Sphk2. In some embodiments, the method comprises enhancing an