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WO2025138225A1 - Système de thérapie de transplantation mitochondriale et son utilisation - Google Patents

Système de thérapie de transplantation mitochondriale et son utilisation Download PDF

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Publication number
WO2025138225A1
WO2025138225A1 PCT/CN2023/143578 CN2023143578W WO2025138225A1 WO 2025138225 A1 WO2025138225 A1 WO 2025138225A1 CN 2023143578 W CN2023143578 W CN 2023143578W WO 2025138225 A1 WO2025138225 A1 WO 2025138225A1
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mitochondrial
optionally
damage
disease
cells
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PCT/CN2023/143578
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English (en)
Chinese (zh)
Inventor
刘兴国
杜世伟
龙琪
周艳双
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Guangzhou Institute of Biomedicine and Health of CAS
Guangzhou Medical University
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Guangzhou Institute of Biomedicine and Health of CAS
Guangzhou Medical University
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Priority to PCT/CN2023/143578 priority Critical patent/WO2025138225A1/fr
Publication of WO2025138225A1 publication Critical patent/WO2025138225A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues

Definitions

  • the present disclosure relates to the technical field of biomedical materials, and in particular, to a mitochondrial transplantation treatment system and uses thereof.
  • Mitochondria are organelles that supply energy in eukaryotic cells and play an important role in ATP synthesis, cell metabolism, growth and development, and aging and death. Mitochondria are semi-autonomous replicating organelles in eukaryotic cells. Human mitochondria contain approximately 16.5 kb of circular double-stranded DNA (mtDNA), which can encode 13 proteins, 2 rRNAs, and 22 tRNAs. mtDNA encodes the core components of mitochondrial respiratory complexes I-IV, which play a key role in maintaining normal cell life activities. Mitochondrial oxidative phosphorylation places mtDNA in a highly reactive oxygen environment and lacks the protection of histones.
  • mtDNA circular double-stranded DNA
  • mtDNA is particularly susceptible to oxidative stress damage, leading to mitochondrial dysfunction.
  • Gene mutations can also occur during mitochondrial DNA replication, which can be cleared by mitochondrial autophagy or mitochondrial fusion and fission. In dysfunctional or damaged mitochondria, mtDNA mutations will accumulate in the cell, leading to an increase in the mutation rate.
  • Mitochondrial DNA has a threshold effect. When the mtDNA mutation rate reaches the threshold, mitochondrial function is severely damaged, leading to cell death or tissue lesions, which may eventually lead to mitochondrial diseases. Dysfunction of mitochondria, especially their metabolic activities, has been implicated in many diseases, including metabolic disorders, neurodegenerative diseases and cancer, as well as the aging process.
  • Mitochondrial disease is a hereditary disease, a large part of which is transmitted through mtDNA mutations, with a prevalence of about 1/5,000. In the disease state, mutated mtDNA often coexists with wild-type mtDNA. The severity of the disease caused by mtDNA mutations is related to the mutation rate. There is a threshold effect. The occurrence of some diseases must have more than 60% of mtDNA mutations, which is a clear feature of mtDNA diseases. Currently, many researchers are trying to reduce the mtDNA mutation rate below the threshold to treat these basically incurable diseases. Mitochondrial diseases are clinically heterogeneous and tissue-specific, and mutations in the same mitochondrial protein complex can lead to different disease phenotypes.
  • mitochondrial diseases such as idebenone for the treatment of Leber hereditary optic neuropathy (LHON), and sodium valproate for the treatment of myoclonic epilepsy in mitochondrial diseases.
  • Mitochondrial replacement (MRT) makes it possible for parents with mitochondrial diseases to have healthy offspring.
  • mitochondrial diseases such as small molecule drugs and gene therapy targeting the mitochondrial genome.
  • mitochondrial transplantation technology to transplant healthy mitochondria into damaged cells or organs to restore cell energy metabolism and cure diseases.
  • mitochondrial transplantation has achieved many positive results in the treatment or intervention of various diseases, such as neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, sarcopenia and heart transplantation.
  • the current mitochondrial transplantation technology has many shortcomings, such as inappropriate vector selection resulting in a small number of healthy mitochondria, low efficiency of mitochondria entering the vector, or damage to the structure or function of mitochondria. Mitochondrial transplantation technology has been further improved.
  • the first aspect of the present disclosure provides a mitochondrial transplantation therapy system.
  • the mitochondrial transplantation therapy system comprises:
  • the transfer vector includes at least one of an artificial lipid vesicle, a cell-derived vesicle, and an exosome.
  • the cell membrane is a semipermeable membrane composed of phospholipid bimolecules as a scaffold, which provides a relatively independent space for the life activities of the cell and ensures the normal life activities of the cell.
  • proteins, lipids and sugars on the surface of the cell membrane, which have good fluidity and can form vesicles for transportation inside and outside the cell.
  • Red blood cells are distributed in large quantities in the blood, can transport O2 and CO2 , and play an important role in the process of cell respiration. During the maturation of red blood cells, the nucleus and organelles slowly disappear.
  • Parkinson's disease is a neurological disease in middle-aged and elderly people, and is associated with damage to dopaminergic neurons in the substantia nigra.
  • the neurotoxic substance 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can be converted into MPP + after entering the brain.
  • MPP + can selectively enter the substantia nigra dopamine neurons in the midbrain, inhibit the activity of mitochondrial respiratory chain complex I, trigger mitochondrial oxidative stress, lead to dopamine neuron death, and induce Parkinson's symptoms. Therefore, mitochondrial damage may also be one of the causes of Parkinson's disease.
  • the inventors used MPTP to construct a Parkinson's mouse model to explore whether the mitochondrial transplantation treatment system can work in vivo.
  • the results showed that the mitochondrial transplantation treatment system provided by the present disclosure can repair the motor ability of Parkinson's mice and the neurons are also restored.
  • At least one of artificial lipid vesicles, cell-derived vesicles, and exosomes is used as a transfer carrier.
  • the developed mitochondrial transplantation treatment system is simple to operate and can efficiently and quickly transfer mitochondria into a large number of cells at the same time, thereby achieving the purpose of mitochondrial transfer.
  • the transfer vector is a cell membrane structure or a lipid vesicle structure derived from red blood cells.
  • the mitochondrial transplantation treatment system provided by the present disclosure is obtained by assembling lipid vesicles prepared from red blood cell membranes and extracted mitochondria.
  • the inventors found in experiments that after incubating individual mitochondria with other cells, mitochondria can enter cells in small amounts, but under time series observation, the mitochondria are spherical in the cells, do not move, and the cell state does not improve.
  • mitochondria wrapped by the specific transfer vector of the present disclosure can efficiently enter cells and exert the functions and effects of mitochondria.
  • the mitochondria are isolated from mammalian cells.
  • the second aspect of the present disclosure provides a medicine.
  • the medicine includes the mitochondrial transplantation treatment system described in the first aspect.
  • the third aspect of the present disclosure provides use of the mitochondrial transplantation treatment system described in the first aspect and the drug described in the second aspect in the preparation of a drug for repairing mitochondrial damage.
  • the inventors have discovered that after incubating the mitochondrial transplantation treatment system disclosed herein with mitochondrial damaged cells, normal mitochondria can be efficiently and quickly transferred into a large number of recipient cells to achieve mitochondrial transplantation.
  • the transplanted mitochondria restore the network structure within the cells and have mitochondrial function, thereby repairing the mitochondrial damage of the recipient cells.
  • the mitochondrial damage includes mitochondrial function damage and mtDNA mutation.
  • the mitochondrial function damage includes mitochondrial structure damage and mitochondrial metabolism damage.
  • the mtDNA mutation includes mtDNA point mutation and mtDNA deletion mutation.
  • the mitochondrial transplantation treatment system can repair mtDNA damage mutations.
  • the inventors found through experiments that the function of transplanted mitochondria was detected in mtDNA-removed cells ( ⁇ 0 cells) and mtDNA large fragment-deficient cells GM04516.
  • mitochondrial transplantation the mitochondrial morphology, mtDNA quantity and membrane potential of ⁇ 0 cells were restored, mitochondrial ATP production was significantly restored, and the transcription level of mtDNA-encoded proteins was also restored.
  • mitochondrial transplantation the mitochondrial morphology of GM04516 cells was restored, mitochondrial ATP production was significantly restored, and the transcription level of mtDNA-encoded proteins was also restored.
  • the fourth aspect of the present disclosure provides use of the mitochondrial transplantation treatment system described in the first aspect and the drug described in the second aspect in the preparation of drugs for repairing diseases related to mitochondrial dysfunction.
  • the mitochondrial transplantation treatment system can repair diseases related to mitochondrial dysfunction. For example, it can alleviate Parkinson's disease caused by mitochondrial dysfunction.
  • the inventors found through experiments that the small molecule drug MPTP was used to induce mitochondrial damage and construct a Parkinson's mouse model; then the mitochondrial transplantation treatment system disclosed in the present disclosure can repair the mitochondrial damage of Parkinson's mice.
  • the results showed that dopaminergic neurons and mouse motor energy The strength was significantly restored, indicating that the developed mitochondrial transplantation therapy system can be used to repair mitochondrial damage.
  • the mitochondrial dysfunction is caused by damage to the mitochondrial respiratory chain, abnormal proteins encoded by nuclear genes, and changes in physical and chemical properties.
  • the mitochondrial dysfunction-related diseases include at least one of nervous system diseases caused by mitochondrial dysfunction, hearing loss-related diseases, optic neuropathy, muscle lesions, cardiac function damage, liver function damage, kidney function damage, pancreatic function damage, gastrointestinal function damage, metabolic diseases, reproductive diseases, and bone lesions.
  • the nervous system disease comprises at least one of neuronal developmental delay, Parkinson's disease, Alzheimer's disease, stroke, epilepsy, migraine and amyotrophic lateral sclerosis.
  • the hearing impairment-related disease includes at least one of deafness and sensorineural hearing loss.
  • the optic neuropathy includes at least one of progressive external ophthalmoplegia, optic atrophy, and retinitis pigmentosa.
  • the muscle lesions include at least one of progressive muscle weakness and atrophy, sarcopenia, and exercise intolerance.
  • the cardiac function damage includes at least one of cardiomyopathy and myocardial conduction defect.
  • the liver function damage includes at least one of liver failure, liver damage, fatty liver, and cirrhosis.
  • the liver function impairment includes at least one of Fanconi syndrome, renal tubular acidosis, glomerulosclerosis, renal failure, and adrenal cortical insufficiency.
  • the pancreatic function impairment includes at least one of diabetes and pancreatitis.
  • the gastrointestinal function impairment includes at least one of pseudo-intestinal obstruction and gastrointestinal motility disorder.
  • the metabolic disease includes at least one of aging, obesity, hyperglycemia, dyslipidemia, insulin resistance and cardiovascular disease.
  • the reproductive disease includes at least one of premature ovarian failure and male infertility.
  • the bone lesions include at least one of kyphoscoliosis, dwarfism, and bone marrow failure.
  • the mitochondria can be isolated from mammalian cells, for example, the mammalian cells can be human cells.
  • the mitochondrial transplantation therapy system is used to prolong the preservation time of transplanted organs, including at least one of heart, liver, lung and kidney transplantation.
  • the mitochondrial transplantation therapy system is used for at least one form of diseases such as weight loss and organ metabolism regulation.
  • the present disclosure provides a method for obtaining heterologous mitochondrial hybrid cells, the method comprising:
  • the aforementioned mitochondrial transplantation therapeutic system is co-incubated with recipient cells containing autologous mitochondria, and the heterologous mitochondria contained in the mitochondrial transplantation therapeutic system enter the recipient cells, so as to obtain heterologous mitochondrial hybrid cells.
  • the new mitochondrial transplantation treatment system provided by the present disclosure can repair the mitochondria of cells with mtDNA removed; repair the mitochondrial function of cells with mitochondrial DNA deletion; and repair the symptoms of Parkinson's mice caused by mitochondrial dysfunction
  • the specific mitochondrial transplantation treatment system provided by the present disclosure can maintain the morphology and function of the healthy mitochondria it encapsulates, and can efficiently enter the recipient cells and play the role of mitochondria.
  • the mitochondrial transplantation treatment system provided by the present disclosure can be used to repair all diseases related to mitochondrial dysfunction, such as nervous system diseases caused by mitochondrial dysfunction, hearing loss-related diseases, optic neuropathy, muscle lesions, heart function damage, liver function damage, kidney function damage, pancreatic function damage, gastrointestinal function damage, metabolic diseases, reproductive diseases, bone lesions, etc.
  • diseases related to mitochondrial dysfunction such as nervous system diseases caused by mitochondrial dysfunction, hearing loss-related diseases, optic neuropathy, muscle lesions, heart function damage, liver function damage, kidney function damage, pancreatic function damage, gastrointestinal function damage, metabolic diseases, reproductive diseases, bone lesions, etc.
  • mitochondrial transplantation can also be used for skin repair, improving ischemia-reperfusion injury during organ transplantation, prolonging the preservation time of transplanted organs, treating or alleviating organ metabolic regulation abnormalities, etc. Therefore, the mitochondrial transplantation treatment system disclosed in the present disclosure can also treat these diseases.
  • the inventors found that different types of mitochondria were transplanted into different types of cells, for example, HeLa and Cos7 cell mitochondria were transplanted into HeLa, Cos7, U20S, and 3T3 cells. It was found that mitochondria of the same species can function in cells of the same species. Due to the heterogeneity of mitochondria, preferably, the cells from which the mitochondria used for transplantation are derived are consistent with or similar to the cells to be repaired. There are differences in the number and metabolic levels of mitochondria contained in cells in different parts, and cells with high similarity are selected as mitochondrial donors as much as possible.
  • the mitochondrial transplantation therapy system was constructed according to the following method:
  • mice Take 20 C57BL/6J mice from the experimental animal center and use 1.25% Avertin (0.2mL/10g) for intraperitoneal anesthesia. Observe the anesthesia state of the mice and use a glass capillary blood collection tube to collect blood from the eye socket. About 100-200 ⁇ L of blood can be collected from each mouse. In order to prevent coagulation, an appropriate amount of anticoagulant can be added to the collection tube. Centrifuge the collected blood at 800g for 10min, gently aspirate the supernatant, and obtain a dark red cell precipitate. Add an appropriate amount of pre-cooled PBS solution to the blood cell precipitate, blow and suspend, filter the cells with a 0.45 ⁇ m filter, and remove the agglutinated cells in the precipitate.
  • Avertin 0.2mL/10g
  • any cells of the corresponding species including primary cells or cell lines, and culture and expand them in vitro.
  • the cells grow to 5 ⁇ 10 7 , use 0.25% trypsin to digest and collect the cells, centrifuge at 300g for 3min, remove the upper culture medium, add DPBS solution to resuspend the cells, centrifuge at 300g for 3min, and aspirate the supernatant.
  • Add an appropriate amount of mitochondrial extraction solution place on ice for 10-20min, use a 5mL syringe to blow the cells on ice 25-35 times, and freeze at 800g. Centrifuge for 5 minutes.
  • the extracted mitochondria and artificial lipid vesicles were mixed evenly and stirred for 1 hour using a magnetic stirrer.
  • the mixed solution was centrifuged at 800 g for 5 minutes, and the supernatant was removed to obtain the encapsulated mitochondrial transplantation therapy system as shown in FIG1 .
  • the mitochondria After being wrapped by the cell membrane, the mitochondria enter the recipient cell through endocytosis, and after membrane fusion, the mitochondria are released into the cell.
  • the fluorescent proteins EGFP and DsRed are used to mark the mitochondria respectively.
  • the fluorescent mitochondria After the cells are expanded and cultured, the fluorescent mitochondria are extracted. After the fluorescent mitochondria are transplanted into the cells, the exogenous mitochondria are detected by taking pictures of living cells to see whether they can survive in the cells. HeLa cells were selected for the import experiment. As shown in Figure 2a, DsRed-labeled mitochondria were extracted from HeLa mtDsRed cells and transplanted into HeLa mtGFP cells. It can be observed that most of the transplanted mitochondria are spherical, and some of the mitochondria are restored to linear.
  • Mitochondria marked with EGFP or DsRed were extracted, and they were assembled with artificial lipid vesicles derived from red blood cells according to the method of Example 1. After the assembled mitochondrial transplantation treatment system was used to transplant fluorescent mitochondria into the cells, the exogenous mitochondria were detected by taking photos of living cells to see whether they could survive in the cells.
  • mitochondrial membrane potential fluorescent reagent TMRM staining was used, as shown in b in Figure 3, and after 1-7 days of transplantation, the morphology and membrane potential of the mitochondria were restored, proving that the mitochondrial metabolic function was restored.
  • qPCR was used to detect the relative copy number of mtDNA, and it was found that the copy number of mtDNA was well restored after 24 hours of mitochondrial transplantation treatment disclosed in the present invention (c in Figure 3).
  • mitochondrial-related proteins TFAM and Tom20 were used to evaluate the number and transcription level of mitochondria. Seven days after transplantation, the expression levels of TFAM and Tom20 proteins increased, preliminarily indicating that the number and transcription level of mitochondria in ⁇ 0 cells were restored (Fig.
  • the mitochondrial transplantation treatment system disclosed in the present invention can effectively repair the mitochondrial function of mitochondrial-deficient cells.
  • mtDNA mitochondrial DNA
  • mutations and deletions of mtDNA may occur, thereby affecting mitochondrial function and ultimately leading to mitochondrial diseases.
  • the inventors selected GM04516 with a 7031bp mtDNA deletion. cells (purchased from Coriell Institute), the specific deletion fragment is shown in Figure 4a, to explore whether the mitochondrial transplantation therapy system has a repair effect in the mutant cell line.
  • mitochondria labeled with DsRed were extracted from the cells, and the transplantation treatment system disclosed in the present invention (the transplantation treatment system assembled in Example 3) was used to transfer the mitochondria into GM04516 cells. After 24 hours of transplantation treatment disclosed in the present invention, the mitochondria were labeled using the mitochondrial fluorescent dye MitoTracker deep red, and it was observed that most of the mitochondria transplanted into GM04516 were spherical, and a small number of mitochondria returned to linearity (Fig. 4b).
  • GM04516 cells were collected 7 days after transplantation, and after electron microscopy samples were prepared, the morphology of the mitochondria after transplantation was observed using a transmission electron microscope. It can be observed from Fig. 4c that the GM04516 cells with large mtDNA fragment deletions had abnormal ultrastructures such as the inner cristae of the mitochondria, and 7 days after treatment with the mitochondrial transplantation treatment system disclosed in the present invention, the clear ultrastructure of the inner cristae of the mitochondria could be clearly observed, and the mitochondrial morphology returned to normal. Transmission electron microscopy results showed that transplanting normal mitochondria into mitochondrially damaged cells through the mitochondrial transplantation therapy system can accelerate the repair of damaged mitochondria.
  • the inventor After treatment with the mitochondrial transplantation treatment system disclosed in the present invention, the inventor detected an increase in the number of mtDNA copies in GM04516 cells (e in FIG. 4 ). In order to verify whether the increased mtDNA would affect mtDNA transcription, qPCR was used to detect the transcription of mtDNA. As shown in FIG. 4 f, 24 hours after transplantation of mitochondria, the transcription levels of proteins and rRNA encoded by mitochondrial DNA were significantly increased, and the transcription levels of proteins ATP6, ND3, DN4L, ND4, ND5, ND6 and CYTB encoded by the missing fragments were significantly increased, indicating that the mitochondrial transplantation treatment system disclosed in the present invention can effectively improve the mitochondrial function in cells with large mitochondrial DNA fragment deletions.

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Abstract

La présente divulgation concerne le domaine technique des matériaux biomédicaux, et en particulier un système de thérapie de transplantation mitochondriale et son utilisation. Le système de thérapie de transplantation mitochondriale selon la présente divulgation comprend : des mitochondries obtenues par isolation ; et un support de transfert. Le système de thérapie de transplantation mitochondriale est obtenu par assemblage des mitochondries et du support de transfert. Le support de transfert comprend une vésicule lipidique artificielle et/ou une vésicule dérivée d'une membrane cellulaire et/ou un exosome. Le système de thérapie de transplantation mitochondriale a un procédé de préparation simple, et permet une administration efficace et rapide de mitochondries saines dans des cellules ou des tissus en même temps, ce qui permet de réparer la fonction mitochondriale des cellules endommagées par les mitochondries. Le système de thérapie de transplantation mitochondriale a le potentiel de traiter des maladies associées provoquées par un dysfonctionnement mitochondrial.
PCT/CN2023/143578 2023-12-29 2023-12-29 Système de thérapie de transplantation mitochondriale et son utilisation Pending WO2025138225A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180071337A1 (en) * 2007-05-02 2018-03-15 The Mclean Hospital Corporation Methods and compositions for mitochondrial replacement therapy
CN113122497A (zh) * 2021-04-26 2021-07-16 重庆理工大学 工程化线粒体及其制备方法
CN114699430A (zh) * 2022-04-12 2022-07-05 重庆理工大学 线粒体及其在胰腺炎中的应用和应用方法
CN115068502A (zh) * 2021-03-12 2022-09-20 深圳市脉唐生物科技有限公司 一种线粒体递送系统及其制剂
CN116478920A (zh) * 2023-05-05 2023-07-25 重庆理工大学 一种离体线粒体的体外储存方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180071337A1 (en) * 2007-05-02 2018-03-15 The Mclean Hospital Corporation Methods and compositions for mitochondrial replacement therapy
CN115068502A (zh) * 2021-03-12 2022-09-20 深圳市脉唐生物科技有限公司 一种线粒体递送系统及其制剂
CN113122497A (zh) * 2021-04-26 2021-07-16 重庆理工大学 工程化线粒体及其制备方法
CN114699430A (zh) * 2022-04-12 2022-07-05 重庆理工大学 线粒体及其在胰腺炎中的应用和应用方法
CN116478920A (zh) * 2023-05-05 2023-07-25 重庆理工大学 一种离体线粒体的体外储存方法

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