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CN-122005868-A - Use of base editing system in combination with CSF1 inhibitor in preparation of drug for treating Alzheimer disease

CN122005868ACN 122005868 ACN122005868 ACN 122005868ACN-122005868-A

Abstract

The invention relates to a composition and application of the composition in preparing medicines for treating Alzheimer's disease, wherein the composition comprises hematopoietic stem cells modified by an adenine base editing system and a colony stimulating factor 1 receptor inhibitor, the application method of the medicines for treating Alzheimer's disease comprises the steps of S1, using the colony stimulating factor 1 receptor inhibitor to deplete microglial cells in brain, S2, performing marrow cleaning pretreatment, S3, transplanting the hematopoietic stem cells modified by the adenine base editing system, wherein the adenine base editing system is used for correcting R47H site mutation of TREM2 genes in the hematopoietic stem cells, and experiments prove that the base editing system and the CSF1 inhibitor can be combined to replace microglial cells in brain, reduce Aβ load in brain, relieve neuroinflammation and improve cognitive impairment, and the effect is obviously superior to that of a monotherapy.

Inventors

  • WANG YANJIANG
  • CHENG TIANLIN
  • YU ZHONGYUAN
  • LIU XIAOYU
  • TAN QI
  • TANG JINYI
  • YUAN ZIYU

Assignees

  • 中国人民解放军陆军特色医学中心
  • 复旦大学

Dates

Publication Date
20260512
Application Date
20260325

Claims (10)

  1. 1. A composition comprising (a) a hematopoietic stem cell modified by an adenine base editing system capable of correcting adenine at the R47H mutation site in the TREM2 gene to guanine, and (b) a colony stimulating factor 1 receptor inhibitor.
  2. 2. The composition of claim 1, wherein the adenine base editing system comprises an adenine base editor selected from one of TeABE-1249 (F148A), teABE-1249 (V82G), teABE-770, the nucleotide sequence encoding the TeABE-1249 (F148A) is shown in SEQ ID No.3, the nucleotide sequence encoding the TeABE-1249 (V82G) is shown in SEQ ID No.4, and the nucleotide sequence encoding the TeABE-770 is shown in SEQ ID No. 5.
  3. 3. The composition of claim 1, wherein the adenine base editing system comprises an sgRNA selected from one of sgRNA1 and sgRNA2, wherein the sequence encoding the sgRNA1 is shown in SEQ ID No.1, and the sequence encoding the sgRNA2 is shown in SEQ ID No. 2.
  4. 4. The composition of claim 1, wherein the colony stimulating factor 1 receptor inhibitor is PLX5622.
  5. 5. The composition of claim 1, wherein the hematopoietic stem cells are derived from the patient himself.
  6. 6. Use of a composition according to any one of claims 1 to 5 for the preparation of a medicament for the treatment of alzheimer's disease.
  7. 7. The use according to claim 6, wherein the method of using the medicament for treating alzheimer's disease comprises the steps of: S1, using a colony stimulating factor 1 receptor inhibitor to deplete microglial cells in the brain; S2, performing marrow cleaning pretreatment; S3, transplanting hematopoietic stem cells modified by an adenine base editing system, wherein the adenine base editing system is used for correcting R47H site mutation of TREM2 genes in the hematopoietic stem cells.
  8. 8. The use according to claim 6 or 7, wherein the medicament is capable of reducing the area of β -amyloid in the brain of the patient.
  9. 9. The use according to claim 6 or 7, wherein the medicament is capable of increasing the proportion of disease-associated microglia in the patient.
  10. 10. The use according to claim 6 or 7, wherein the medicament is capable of alleviating neuroinflammation in a patient.

Description

Use of base editing system in combination with CSF1 inhibitor in preparation of drug for treating Alzheimer disease Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to application of a base editing system and a CSF1 inhibitor in preparation of a medicine for treating Alzheimer disease. Background Alzheimer's disease is a complex neurodegenerative disease whose traditional pathological cognition has long been focused on abnormal deposition of beta amyloid (Abeta) in the central nervous system of the brain and neurofibrillary tangles formed by hyperphosphorylation of Tau protein. Currently, many research and drug development strategies are focused mainly on directly clearing aβ plaques in the brain or inhibiting Tau protein pathology. However, in recent years a series of important clinical and preclinical studies have shown that Alzheimer's disease is far from an isolated central nervous system disease, but should be considered as a systemic disorder involving complex interactions of the central and peripheral immune systems. Under this emerging framework of cognition, brain-resident immune cell microglial dysfunction has been demonstrated to be a key element driving disease progression, whereas the functional status of myeloid cell triggering receptor 2 (TREM 2) is attractive. The R47H missense mutation on the TREM2 gene is a strong genetic risk factor for Alzheimer's disease which has been clearly confirmed by whole genome association studies. This mutation does not lead to a complete loss of protein function but rather to a significant decrease in its ligand binding capacity, thereby compromising downstream signaling pathway activation. Microglia with impaired TREM2 function in the central nervous system exhibit reduced clearance of the envelope of aβ plaques, reduced metabolic adaptation and a shift to neuroprotective phenotypes, ultimately exacerbating neuroinflammation and neuronal damage. Notably, this pathological effect is not limited to the brain. In the peripheral system TREM2 is also highly expressed in mononuclear phagocytes, particularly blood mononuclear cells, which constitute the first line of defense in peripheral immune surveillance of AD. Monocytes carrying the R47H mutation also have phagocytic dysfunction, which is significantly less able to clear aβ in circulation than wild-type cells, resulting in a blocked peripheral aβ clearance pathway, possibly indirectly increasing aβ loading to the hub. Thus, the TREM 2R 47H mutation actually promotes the pathological occurrence and development of AD together at the system level by impairing the dual immune function of peripheral monocytes and central microglia. In the face of this systemic immune dysfunction, existing intervention strategies present significant limitations. Monoclonal antibody therapy against aβ can reduce plaque burden in the brain to some extent, but is ineffective against sustained immune cell intrinsic function defects determined by genetic factors, and has limited regulatory effects on the peripheral immune system and an unknown mechanism. On the other hand, the traditional allogeneic hematopoietic stem cell transplantation strategy aiming at comprehensively replacing the defective immune cells has extremely dark application prospect in chronic and non-malignant diseases such as Alzheimer disease due to the accompanying strong immune rejection risk, difficult typing and high treatment cost. More importantly, even if the transplantation disorder can be overcome, the simple bone marrow replacement mainly affects monocytes in the peripheral circulation, and peripheral monocytes derived from the transplantation are extremely difficult to effectively infiltrate the brain parenchyma and replace the dysfunctional microglia due to the existence of the blood brain barrier and the strong self-sustaining ability of resident microglia in the brain. This means that the prior art is difficult to achieve synchronous correction of immunodeficiency caused by the same gene mutation in both peripheral and central compartments, which constitutes a critical bottleneck to be broken through in the current field of accurate immunotherapy for AD. Disclosure of Invention Aiming at the defects existing in the prior art, the invention provides application of a base editing system and a CSF1 inhibitor in combination in preparation of a drug for treating Alzheimer disease. The technical scheme of the invention is as follows: A composition comprising (a) a hematopoietic stem cell modified with an adenine base editing system capable of correcting adenine at the R47H mutation site in the TREM2 gene to guanine, and (b) a colony stimulating factor 1 receptor inhibitor. Further, the adenine base editing system comprises an adenine base editor, wherein the adenine base editor is selected from one of TeABE-1249 (F148A), teABE-1249 (V82G) and TeABE-770, the nucleotide sequence for encoding TeABE-1249