KR20240062036A - Composition containing colchicine and metformin for preventing and treating neurodegenerative diseases - Google Patents
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Abstract
본 발명은 콜치신 또는 이의 약학적으로 허용 가능한 염 및 메트포르민 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 하는 복합제를 이용한 퇴행성 신경계 질환 특히 근위축성 측삭 경화증 등과 같은 TAR DNA-결합 단백질 43 (TDP-43)의 응집체 형성과 관련된 질병이나, 이러한 상태의 발병 또는 발달 등을 치료, 예방, 억제 및 개선 또는 감속시키기 위한 치료용 조성물에 관한 것이다.
상기와 같은 TDP-43 단백질 등과 관련된 질병은 전측두엽 치매 (FTD: Frontotemporal dementia), 근위축성 측삭 경화증 (ALS: Amyotrophic lateral sclerosis), 알츠하이머병 (AD: Alzheimer's disease), 파킨슨병 (PD: Parkinson's disease), 만성 외상성 뇌병증 (CTE: Chronic traumatic encelopathy) 및 변연계-우세 연령-관련 TDP-43 뇌병증 (LATE: Limbic-predominant age-related TDP-43 encephalopathy) 등을 포함하며, TDP-43과 관련된, 특히 TDP-43 응집체와 관련된 질환이나 장애 및 이상, 또는 TDP-43 단백질병증 (Proteinopathy) 등을 포함한다.
본 발명의 발명자들은 상기와 같은 퇴행성 질환의 치료제로서 종래기술에서는 사용하지 않았던 약물인 콜치신과 메트포르민을 혼합한 복합제를 사용함으로써 상기와 같은 질병을 치료 또는 예방할 수 있다는 것을 확인하였다.
The present invention is a treatment for degenerative neurological diseases, especially TAR DNA-binding protein 43 (TDP- 43) It relates to a therapeutic composition for treating, preventing, suppressing, improving or slowing down diseases related to aggregate formation or the onset or development of such conditions.
Diseases related to the above TDP-43 protein include frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD). , Chronic traumatic encephalopathy (CTE) and Limbic-predominant age-related TDP-43 encephalopathy (LATE), etc., related to TDP-43, especially TDP- 43 Includes diseases, disorders and abnormalities related to aggregates, or TDP-43 proteinopathy.
The inventors of the present invention confirmed that the above-mentioned diseases can be treated or prevented by using a combination of colchicine and metformin, a drug that was not used in the prior art, as a treatment for the above-mentioned degenerative diseases.
Description
본 발명은 콜치신 또는 이의 약학적으로 허용 가능한 염 및 메트포르민 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 하는 복합제를 이용한 TAR DNA-결합 단백질 43 (TDP-43)의 응집체 형성과 관련된 질병이나, 이러한 상태의 발병 또는 발달 등을 치료, 예방, 억제 및 개선 또는 감속시키기 위한 치료용 조성물에 관한 것이다. The present invention is a disease associated with the formation of aggregates of TAR DNA-binding protein 43 (TDP-43) using a complex agent containing colchicine or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof as active ingredients, It relates to therapeutic compositions for treating, preventing, inhibiting, ameliorating or slowing down the onset or development of such conditions.
상기와 같은 TDP-43 단백질 등과 관련된 질병은 주로 퇴행성 신경계 질환인데, 이러한 퇴행성 질환에 해당되는 질병은 전측두엽 치매 (FTD: Frontotemporal dementia), 근위축성 측삭 경화증 (ALS: Amyotrophic lateral sclerosis), 알츠하이머병 (AD: Alzheimer's disease), 파킨슨병 (PD: Parkinson's disease), 만성 외상성 뇌병증 (CTE: Chronic traumatic encelopathy) 및 변연계-우세 연령-관련 TDP-43 뇌병증 (LATE: Limbic-predominant age-related TDP-43 encephalopathy) 등을 포함하며, TDP-43과 관련된, 특히 TDP-43 응집체와 관련된 질환이나 장애 및 이상, 또는 TDP-43 단백질병증 (Proteinopathy) 등을 포함한다. Diseases related to the TDP-43 protein as described above are mainly degenerative nervous system diseases, and diseases that fall under these degenerative diseases include frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease ( AD: Alzheimer's disease), PD: Parkinson's disease, CTE: Chronic traumatic encephalopathy, and Limbic-predominant age-related TDP-43 encephalopathy (LATE) and the like, and includes diseases, disorders and abnormalities related to TDP-43, especially TDP-43 aggregates, or TDP-43 proteinopathy.
본 발명의 발명자들은 상기와 같은 퇴행성 질환의 치료제로서 종래기술에서는 사용하지 않았던 약물인 콜치신과 메트포르민을 혼합한 복합제를 사용함으로써 상기와 같은 질병을 치료 또는 예방할 수 있다는 것을 확인하였다. The inventors of the present invention confirmed that the above-mentioned diseases can be treated or prevented by using a combination of colchicine and metformin, a drug that was not used in the prior art, as a treatment for the above-mentioned degenerative diseases.
파킨슨병, 알츠하이머 치매, 뇌졸중 등으로 대표되는 퇴행성 신경계 질환은 신경세포 손상과 소실로 이어지는 세포죽음이 그 궁극적 원인인 것으로 알려져 있다. 예컨대, 파킨슨병의 경우에는 중뇌의 흑색질에 있는 도파민성 신경세포들이 선택적으로 소실됨으로써 운동 기능 조직에 관여하는 기저핵의 기능 이상을 초래하여 지속적 떨림, 경직, 서동, 자세 불안정 등의 운동기능 장애를 유발한다. It is known that the ultimate cause of degenerative neurological diseases such as Parkinson's disease, Alzheimer's dementia, and stroke is cell death leading to nerve cell damage and loss. For example, in the case of Parkinson's disease, dopaminergic neurons in the substantia nigra of the midbrain are selectively lost, resulting in dysfunction of the basal ganglia involved in motor function organization, causing motor dysfunction such as persistent tremor, rigidity, bradykinesia, and postural instability. do.
상기와 같은 퇴행성 신경질환에서 본 발명의 발명자들은 콜치신과 메트포르민을 혼합한 복합제가 TDP-43 단백질과 관련이 높은 근위축성 측삭 경화증 (ALS: Amyotrophic lateral sclerosis), 일명 루게릭병에 특히 효과가 좋다는 것을 확인하였다. In the above-described neurodegenerative diseases, the inventors of the present invention found that a combination of colchicine and metformin was particularly effective in treating amyotrophic lateral sclerosis (ALS: Amyotrophic lateral sclerosis), also known as Lou Gehrig's disease, which is highly related to the TDP-43 protein. Confirmed.
루게릭병 (Lou Gehrig’disease)이라고도 불리는 근위축성 측삭 경화증 (ALS: Amyotrophic lateral sclerosis)은 중추신경계에서 운동신경세포에 점진적인 퇴행이 일어나는 희귀성 신경계 퇴행성 질환으로 운동뉴런에서 신경세포가 사멸되는 것을 특징으로 하고 있다. 루게릭병의 정확한 발병기전 규명 및 치료제에 관한 연구는 아직 명확하게 확인되지는 않았고, 현재 미국 FDA로부터 루게릭병의 치료제로서 허가받은 약물은 리루졸과 에다라본 성분 제제로, 두 약제 모두 환자에서 기대 수명을 몇 개월 연장하거나 초기 단계에서 질병의 진행을 지연시키는 데 도움이 되는 것으로 알려져 있으나, 아직도 루게릭병에 대한 근본적인 치료법은 없다. Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a rare neurodegenerative disease that causes gradual degeneration of motor neurons in the central nervous system and is characterized by death of nerve cells in motor neurons. I'm doing it. Research on the exact pathogenesis and treatment of Lou Gehrig's disease has not yet been clearly confirmed, and the drugs currently approved by the U.S. FDA as a treatment for Lou Gehrig's disease are riluzole and edaravone, both of which have lower life expectancy in patients. Although it is known to help extend the disease by several months or delay the progression of the disease in the early stages, there is still no fundamental cure for Lou Gehrig's disease.
루게릭병 환자의 약 10% 정도가 유전적인 원인을 보이는 것으로 보고되었고, 나머지 환자의 90%의 경우는 면역, 산화독성, 흥분독성, 환경 인자, 또는 단백질의 응집 등이 원인일 것으로 추정하고 있다. It has been reported that approximately 10% of patients with Lou Gehrig's disease have genetic causes, and it is estimated that the remaining 90% of patients may be caused by immunity, oxidative toxicity, excitotoxicity, environmental factors, or protein aggregation.
이 중에서 TDP-43이라는 단백질의 응집이 약 90% 이상의 루게릭 환자에게서 관찰되고, 이러한 현상이 루게릭의 중요한 발병 원인일 것이라는 연구 결과가 다수 보고되고 있다. Among these, aggregation of a protein called TDP-43 is observed in more than 90% of Lou Gehrig's patients, and many studies have reported that this phenomenon is an important cause of Lou Gehrig's disease.
TDP-43은 주로 세포핵에 존재하는데, TDP-43 응집체가 세포질로 축적이 되는 경우에 TDP-43 단백질과 관련되는 병증이 유발되는 것으로 알려져 있고, 이러한 TDP-43의 세포질 내 비정상적인 응집은 최근 변연계 특이 노인성 TDP-43 뇌병증 (LATE) 치매, 알츠하이머성 치매 환자의 뇌에서도 발견되었다. TDP-43 is mainly present in the cell nucleus, and when TDP-43 aggregates accumulate in the cytoplasm, it is known to cause diseases related to the TDP-43 protein. Abnormal aggregation of TDP-43 in the cytoplasm has recently been found to be specific to the limbic system. It was also found in the brains of patients with senile TDP-43 encephalopathy (LATE) dementia and Alzheimer's dementia.
본 발명에서 주 치료대상으로 하는 근위축성 측삭 경화증 (ALS: Amyotrophic lateral sclerosis)에 대한 유효한 치료제 (Treatments)를 개발하는 것은 상기와 같이 아직 ALS 질병을 유발하는 명확한 기전이 확인되지 않아서 제약업계에 상당한 어려움을 주고 있다. Developing effective treatments for amyotrophic lateral sclerosis (ALS), which is the main target of treatment in the present invention, is a significant difficulty for the pharmaceutical industry because a clear mechanism causing ALS disease has not yet been identified as described above. is giving.
릴루졸 (Rilutek, 사노피)과 에다라본 (Radicut, 미쓰비시다나베 파마)은 ALS에 대해 현재까지 유일하게 허가받은 치료제이나, 릴루졸은 중추신경계에서 글루타민산성 신경전달을 차단해 운동 뉴런의 어팝토시스 (Apoptosis, 프로그램된 세포 사망)를 방지하는 신경 보호적 약이며, 에다라본은 자유라디칼 (Free radical)에 의한 산화 스트레스 억제하는 등 이들 치료제는 모두 증상 완화 효과만 확인된 상태이다. Riluzole (Rilutek, Sanofi) and Edaravone (Radicut, Mitsubishi Nabe Pharma) are the only approved treatments for ALS to date, but riluzole blocks glutamatergic neurotransmission in the central nervous system, causing apoptosis (apoptosis) of motor neurons. It is a neuroprotective drug that prevents apoptosis (programmed cell death), and edaravone suppresses oxidative stress caused by free radicals. All of these treatments have only been confirmed to have symptom-relieving effects.
따라서, ALS와 같은 TDP-43 단백질병증 치료에 대한 개선된 요법 (Therapy)을 개발할 필요가 있고, 이러한 효과적인 요법을 개발하면 ALS 질병을 앓는 환자들의 삶의 질 및 수명을 개선하는데 기여할 뿐만 아니라, 그러한 질병들의 비용부담을 낮추는 데도 상당한 도움을 줄 것이다. Therefore, there is a need to develop improved therapies for the treatment of TDP-43 proteinopathies such as ALS, and developing such effective therapies will not only contribute to improving the quality of life and longevity of patients suffering from ALS disease, but also contribute to improving the quality of life and longevity of patients suffering from ALS disease. It will also significantly help reduce the cost burden of diseases.
본 발명에서 제공하는 TDP-43 단백질병증과 관련하여 콜치신과 메트포르민을 유효성분으로 하는 복합제를 이용한 치료 방법에 대해서도 아직까지 연구된 바가 없다. Regarding TDP-43 proteinopathy provided by the present invention, no research has yet been conducted on a treatment method using a combination drug containing colchicine and metformin as active ingredients.
본 발명은 상기와 같이 TDP-43 단백질병증과 관련되는 근위축성 측삭 경화증 (ALS: Amyotrophic lateral sclerosis)을 치료하기 위한 치료제가 부족하고, 상기 질병에 관한 명확한 연구도 충분히 진행되지 않아서 새로운 치료제를 개발하는 것이 상당한 부담이 되는 상황을 해결하기 위한 것이다.The present invention is aimed at developing a new therapeutic agent because there is a lack of therapeutic agents for treating amyotrophic lateral sclerosis (ALS) associated with TDP-43 proteinopathy as described above, and clear research on the disease has not been sufficiently conducted. This is to resolve situations where this is a significant burden.
이에 따라 본 발명에서는 종래의 기술에서는 근위축성측삭경화증의 치료제로서 연구되지 않았던 콜치신과 메트포르민을 혼합한 복합제를 이용하여 상기 질병에 대한 치료효과를 지속적으로 연구한 결과 상기의 복합제가 충분한 효과가 있다는 것을 확인함으로써 본 발명을 완성하게 되었다.Accordingly, in the present invention, a combination of colchicine and metformin, which had not been studied as a treatment for amyotrophic lateral sclerosis in the prior art, was used to continuously study the treatment effect on the disease, and the results showed that the combination was sufficiently effective. By confirming this, the present invention was completed.
중추신경계 (CNS) 및 말초 기관에서 단백질의 병리학적 응집을 특징으로하는 연령-관련 뇌 장애는 전 세계에서 장애 및 사망의 주요 원인 중 하나이다. 알츠하이머병 및 관련 장애에서 가장 잘 특성 분석된 응집체를 형성하는 단백질은 아밀로이드 베타이다. 신경퇴행을 야기하는 다른 질환-관련, 응집-경향 단백질은 비제한적으로 알파-시누클레인 (αSyn: α-Synuclein), 헌팅틴, 육종 융합 (FUS: Fused in sarcoma), C9orf72의 반복 확장 (C9orf72 repeat expansion)의 비통상적인 번역에 의해 생성된 디펩티드 반복 단백질 (DPR: Dipeptide repeat protein), 슈퍼옥시드 디스뮤타제 1 (SOD1), 및 TDP-43이다. 이중 TDP-43 응집체와 관련된 질환은 일반적으로 비제한적으로 ALS 및 FTD를 포함하여 TDP-43 단백질병증으로 열거된다.Age-related brain disorders, characterized by pathological aggregation of proteins in the central nervous system (CNS) and peripheral organs, are one of the leading causes of disability and death worldwide. The best-characterized aggregate-forming protein in Alzheimer's disease and related disorders is amyloid beta. Other disease-related, aggregation-prone proteins that cause neurodegeneration include, but are not limited to, alpha-synuclein (αSyn), huntingtin, Fused in sarcoma (FUS), and C9orf72 repeat. Dipeptide repeat protein (DPR), superoxide dismutase 1 (SOD1), and TDP-43 produced by unconventional translation of expansion). Among these, diseases associated with TDP-43 aggregates are generally listed as TDP-43 proteinopathies, including but not limited to ALS and FTD.
트랜스활성 반응 (TAR: Transactive response) DNA 결합 단백질 43 kDa (TDP-43)은 염색체 1p36.2 (ALS10) 상의 TARDBP 유전자에 의해 코딩된 414-아미노산 단백질이다. TARDBP은 6개의 엑손 (엑손 1은 비-코딩이고; 엑손 2~6은 단백질-코딩임)으로 구성된다. TDP-43은 이종 리보뉴클레오단백질 (hnRNP) RNA 결합 단백질의 패밀리에 속한다. TDP-43은 5개의 기능성 도메인을 포함한다. 2개의 고도로 보존된 6량체 리보뉴클레오단백질 2 (RNP2) 및 8량체 리보뉴클레오단백질1 (RNP1) 영역을 갖는 2개 RNA 인식 모티프 (RRM1 및 RRM2), 결합된 mRNA를 수송하는 핵과 세포질 사이를 왕복할 수 있도록 하는 핵 방출 신호 (NES: Nuclear export signal) 및 핵 국소화 신호 (NLS: Nuclear localization signal) 및 단백질-단백질 상호작용을 매개하는 C-말단의 글리신 풍부 도메인 등으로 구성되어 있다.Transactive response (TAR) DNA binding protein 43 kDa (TDP-43) is a 414-amino acid protein encoded by the TARDBP gene on chromosome 1p36.2 (ALS10). TARDBP consists of six exons (exon 1 is non-coding; exons 2-6 are protein-coding). TDP-43 belongs to the family of heterologous ribonucleoprotein (hnRNP) RNA binding proteins. TDP-43 contains five functional domains. Two RNA recognition motifs (RRM1 and RRM2) with two highly conserved hexameric ribonucleoprotein 2 (RNP2) and octameric ribonucleoprotein 1 (RNP1) regions, transporting bound mRNA between the nucleus and cytoplasm. It is composed of a nuclear export signal (NES: Nuclear export signal) and a nuclear localization signal (NLS: Nuclear localization signal) that allow for shuttling, and a C-terminal glycine-rich domain that mediates protein-protein interactions.
TDP-43은 전사, 스플라이싱, 수송 및 안정화를 포함하는 RNA 처리의 여러 측면에 관련되어 있다. 이는 핵과 세포질 사이를 연속적으로 왕복하는 엄격하게 자가 조절된 발현 수준을 갖는 고도로 보존된 편재적으로 발현된 단백질이지만, 주로 핵 내에 국소화되어 있다. 2006년에, TDP-43은 tau-음성, 유비퀴틴-양성 봉입체(FTLD-TDP로 지칭됨)가 있는 전측두엽 퇴행 (FTLD: Frontotemporal lobar degeneration) 및 근위축성 측삭 경화증 (ALS)의 대부분의 발병에 축적되는 단백질로 확인되었다.TDP-43 is involved in several aspects of RNA processing, including transcription, splicing, transport, and stabilization. It is a highly conserved, ubiquitously expressed protein with a tightly self-regulated expression level that continuously shuttles between the nucleus and cytoplasm, but is primarily localized within the nucleus. In 2006, TDP-43 accumulated in most cases of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) with tau-negative, ubiquitin-positive inclusion bodies (referred to as FTLD-TDP). It was confirmed to be a protein.
TDP-43의 38개의 음성-우성 돌연변이는 산발성 및 가족성 ALS 환자뿐만 아니라 주로 글리신 풍부 도메인에 위치한 유전성 FTD 환자에서 확인되었다. TDP-43은 침강 분석에 의해 나타난 바와 같이 본질적으로 응집되기 쉽고, 이러한 경향은 TDP-43 응집을 임상 질환 징후와 연결하는 ALS-관련 TARDBP 돌연변이의 일부에 의해 추가로 증가된다.Thirty-eight negative-dominant mutations in TDP-43 were identified in patients with sporadic and familial ALS, as well as in patients with hereditary FTD, mainly located in the glycine-rich domain. TDP-43 is inherently prone to aggregation as shown by sedimentation assays, and this tendency is further increased by a subset of ALS-related TARDBP mutations that link TDP-43 aggregation to clinical disease manifestations.
TDP-43 단백질병증 세포모델에서 콜치신과 메트포르민 복합제는 오토파지(Autophagy) 및 샤페론 (Chaperone)의 활성을 증가시켜, TDP-43 단백질의 비정상적인 응집 또는 TDP-43 단백질의 잘못된 위치화 (Mislocalization)에 의한 세포질에서의 축적을 감소시켰으며, 아직까지 이러한 결과에 대해서 보고된 바가 없다. In the TDP-43 proteinopathy cell model, the colchicine and metformin combination increases the activity of autophagy and chaperone, causing abnormal aggregation or mislocalization of the TDP-43 protein. accumulation in the cytoplasm, and this result has not yet been reported.
오토파지는 세포 내 불필요한 단백질이나 비정상적인 세포 소기관을 분해하여 새로운 에너지원으로 재활용하는 세포의 항상성 유지의 중요 기능을 담당하는 것으로 알려져 있고, 또한 이러한 오토파지의 결핍 또는 기능 이상이 뇌 질환을 포함한 다양한 인간의 질병에 밀접하게 연관되어 있다고 알려져 있다. Autophagy is known to play an important role in maintaining cellular homeostasis by breaking down unnecessary proteins or abnormal cell organelles in cells and recycling them as new energy sources, and autophagy deficiency or malfunction can cause various human diseases, including brain diseases. It is known to be closely related to diseases.
한편, 단백질의 오접힘 (Misfolding)을 방지하여 신경세포의 손상 및 사멸을 억제하는데 관여하는 샤페론은 단백질 응집에 대한 방어기작으로 잘 알려져 있으며, 신경퇴행성질환 치료분야에 있어 중요한 타겟으로 여겨져 왔다.Meanwhile, chaperones, which are involved in suppressing damage and death of nerve cells by preventing protein misfolding, are well known as a defense mechanism against protein aggregation, and have been considered important targets in the field of neurodegenerative disease treatment.
본 발명의 본 발명자들은 콜치신 및 메트포르민의 복합 조성물이 신경퇴행성 질환의 주요 병인 인자인 TDP-43 단백질의 비정상적인 응집을 효과적으로 억제할 수 있음을 최초로 규명하였고, 또한 본 발명의 조성물은 퇴행성 신경질환과 관련된 샤페론 및 오토파지를 선택적으로 유도하는 기전을 나타내는 것임을 확인하였다. The inventors of the present invention were the first to demonstrate that a complex composition of colchicine and metformin can effectively inhibit abnormal aggregation of TDP-43 protein, a major etiological factor in neurodegenerative diseases, and furthermore, the composition of the present invention has an effect on neurodegenerative diseases and neurodegenerative diseases. It was confirmed that it represents a mechanism that selectively induces related chaperones and autophagy.
이러한 결과로부터 본 발명의 목적은 TDP-43 단백질과 관련되는 루게릭병 등의 근위축성측삭경화증을 치료 또는 예방하기 위한 콜치신과 메트포르민 복합 조성물을 제공하는 것이다. Based on these results, the purpose of the present invention is to provide a combination composition of colchicine and metformin for treating or preventing amyotrophic lateral sclerosis, such as Lou Gehrig's disease, which is associated with the TDP-43 protein.
또한, 본 발명은 루게릭병으로 대표되는 근위축성측삭경화증 외에도 TDP-43 단백질의 응집과 관련되는 질환은 전측두엽 치매, 근위축성 측삭 경화증, 알렉산더병, 은친화입자병, 괌의 ALS 파킨슨증-치매 복합증, 변연계-우세 연령-관련 TDP-43 뇌병증, 만성 외상성 뇌병증, 페리 증후군, 알츠하이머병, 다운 증후군, 영국 가족성 치매, 헌팅턴병, 마카도 조셉병, 해마 경화증 치매, 봉입체 근염, 테두리 액포가 있는 눈인두 근이영양증, 근섬유 근병증, 외상성 뇌손상, 루이소체가 있는 치매 및 파킨슨병과 같은 퇴행성 신경계 뇌 질환의 예방 또는 치료용 약학 조성물을 제공하는 것을 목적으로 한다.In addition, the present invention provides that, in addition to amyotrophic lateral sclerosis represented by Lou Gehrig's disease, diseases related to aggregation of TDP-43 protein include frontotemporal dementia, amyotrophic lateral sclerosis, Alexander disease, silver particle disease, and ALS Parkinsonism-dementia complex in Guam. , limbic-dominant age-related TDP-43 encephalopathy, chronic traumatic encephalopathy, Perry syndrome, Alzheimer's disease, Down syndrome, British familial dementia, Huntington's disease, Machado Joseph's disease, hippocampal sclerosis dementia, inclusion body myositis, eyes with border vacuoles The purpose is to provide a pharmaceutical composition for preventing or treating degenerative neurological brain diseases such as pharyngeal muscular dystrophy, myofibrillar myopathy, traumatic brain injury, dementia with Lewy bodies, and Parkinson's disease.
본 발명이 해결하고자 하는 기술적 과제는 상기에서 언급한 과제에 제한되지 않으며, 상기 과제와 연관되는 다양한 과제들은 아래의 기재로부터 본 발명에 속하는 기술분야에서 통상의 지식을 가진 자라면 명확하게 이해될 수 있다.The technical problem to be solved by the present invention is not limited to the above-mentioned problem, and various problems related to the above problem can be clearly understood by those skilled in the art from the following description. there is.
상기 목적을 달성하기 위하여, 본 발명은 콜치신 또는 이의 약학적으로 허용 가능한 염 및 메트포르민 또는 이의 약학적으로 허용 가능한 염을 주요 유효성분으로 포함하는 TDP-43 단백질과 관련되는 루게릭병으로 대표되는 근위축성측삭경화증, 파킨슨병, 알츠하이머 치매 또는 픽크병, 크로이츠펠트야콥병, 헌팅톤병, 진행성 핵상마비, 척수소뇌 변성증, 소뇌 위축증, 다발성 경화증, 신경세포의 소실에 의해 발생하는 노인성 치매, 뇌졸중, 외상 후 스트레스 장애, 기억상실증과 같은 퇴행성 신경계 뇌 질환의 예방 또는 치료용 약학 조성물을 제공한다.In order to achieve the above object, the present invention is a disease represented by Lou Gehrig's disease associated with the TDP-43 protein, which contains colchicine or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof as the main active ingredient. Atrophic lateral sclerosis, Parkinson's disease, Alzheimer's dementia or Pick's disease, Creutzfeldt-Jakob disease, Huntington's disease, progressive supranuclear palsy, spinocerebellar degeneration, cerebellar atrophy, multiple sclerosis, senile dementia caused by neuronal loss, stroke, post-traumatic stress. Provided is a pharmaceutical composition for preventing or treating degenerative neurological brain diseases such as disability and amnesia.
또한, 본 발명은 콜치신 또는 이의 약학적으로 허용 가능한 염 및 메트포르민 또는 이의 약학적으로 허용 가능한 염을 주요 유효성분으로 포함하는 상기 질병들의 치료 효과 증진용 약학적 조성물을 제공한다. 상기 치료 효과 증진용 약학 조성물은 본 발명의 대상질환인 루게릭병 등을 예방 및 치료를 위한 치료 보조제와 동일한 개념이다.In addition, the present invention provides a pharmaceutical composition for improving the treatment effect of the above diseases, comprising colchicine or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof as main active ingredients. The pharmaceutical composition for enhancing the therapeutic effect has the same concept as a therapeutic adjuvant for preventing and treating Lou Gehrig's disease, etc., which is the target disease of the present invention.
본 발명의 약학적 조성물은, 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 또는 희석제를 추가로 포함하는 퇴행성 신경계 질환의 치료 또는 예방용 약학 조성물의 형태로 제조될 수 있는데, 상기 담체는 비자연적 담체 (Non-naturally occuring carrier)를 포함할 수 있다. 구체적으로, 상기 약학 조성물은, 각각 통상의 방법에 따라 산제, 환제, 과립제, 정제, 캡슐제, 내용액제, 유제, 현탁액, 에멀젼, 시럽, 에어로졸, 외용제, 멸균된 수용액, 비수성용제, 동결건조제제, 좌제 및 멸균주사제의 형태로 제형화하여 사용될 수 있다.The pharmaceutical composition of the present invention may be prepared in the form of a pharmaceutical composition for the treatment or prevention of degenerative nervous system diseases, which additionally contains an appropriate carrier, excipient, or diluent commonly used in the manufacture of pharmaceutical compositions. It may contain a non-naturally occurring carrier. Specifically, the pharmaceutical compositions can be prepared as powders, pills, granules, tablets, capsules, oral solutions, emulsions, suspensions, emulsions, syrups, aerosols, topical preparations, sterilized aqueous solutions, non-aqueous solvents, and freeze-dried preparations according to conventional methods. , can be formulated and used in the form of suppositories and sterile injections.
본 발명에서 제공하는 약학 조성물은 약리학적으로 허용되는 적절한 담체 외에 퇴행성 신경계 질환에 효과가 있는 멜라토닌 (Melatonin), 크레아틴 (Creatine), 마그네슘, 코엔자임큐텐, 비타민 D, 비타민 B, 비타민 E, L-serine, L-carnitine 및 N-acetylcystein으로 이루어지는 군에서 선택되는 하나 이상의 성분을 더 포함할 수 있다.The pharmaceutical composition provided by the present invention contains, in addition to a suitable pharmacologically acceptable carrier, melatonin, creatine, magnesium, coenzyme Q10, vitamin D, vitamin B, vitamin E, and L-serine, which are effective for degenerative nervous system diseases. , L-carnitine, and N-acetylcysteine.
상기 본 발명의 약학 조성물은 약학적으로 유효한 양으로 투여될 수 있는데, 본 발명의 용어 ‘약제학적으로 유효한 양’이란 의학적 치료 또는 예방에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료 또는 예방하기에 충분한 양을 의미하며, 유효 용량 수준은 질환의 중증도, 약물의 활성, 환자의 연령, 체중, 건강, 성별, 환자의 약물에 대한 민감도, 사용된 본 발명의 조성물의 투여 시간, 투여 경로 및 배출 비율 치료기간, 사용된 본 발명의 조성물과 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하다.The pharmaceutical composition of the present invention can be administered in a pharmaceutically effective amount. As used herein, the term 'pharmaceutically effective amount' refers to the amount used to treat or prevent a disease with a reasonable benefit/risk ratio applicable to medical treatment or prevention. It means a sufficient amount, and the effective dose level is determined by the severity of the disease, the activity of the drug, the patient's age, weight, health, gender, the patient's sensitivity to the drug, the administration time, route of administration, and excretion rate of the composition of the present invention used. It may be determined depending on factors including the duration of treatment, drugs used in combination or concurrently with the composition of the present invention used, and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. And it can be administered single or multiple times. It is important to consider all of the above factors and administer the amount that will achieve the maximum effect with the minimum amount without side effects.
본 발명에서 제공하는 약학 조성물의 투여량은 사용목적, 질환의 중독도, 환자의 연령, 체중, 성별, 기왕력, 또는 유효성분으로서 사용되는 물질의 종류 등을 고려하여 통상의 기술자가 결정할 수 있으나, 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하다. The dosage of the pharmaceutical composition provided in the present invention can be determined by a person skilled in the art taking into account the purpose of use, the degree of addiction of the disease, the patient's age, weight, gender, antecedent history, or the type of substance used as an active ingredient. It is important to consider all of the above factors and administer the amount that will achieve maximum effect with the minimum amount without side effects.
본 발명에서 제공하는 콜치신 또는 이의 약학적으로 허용 가능한 염 및 메트포르민 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 하는 약학 조성물은 상기 두 성분의 시너지 효과로 인하여 TDP-43 단백질의 비정상적 응집 및 잘못된 위치화 (Mislocalization)을 저해하고, 이러한 작용으로 인해서 루게릭병 등 퇴행성 신경계 질환을 효율적으로 예방 또는 치료할 수 있다. The pharmaceutical composition containing colchicine or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof as active ingredients provided by the present invention prevents abnormal aggregation and erroneous aggregation of TDP-43 protein due to the synergistic effect of the two components. It inhibits mislocalization, and this action can effectively prevent or treat degenerative nervous system diseases such as Lou Gehrig's disease.
본 발명에서 제공하는 복합제제는 종래의 고가의 약물을 사용하지 않고도 저용량으로 투여하여도 상기 질병의 예방 또는 치료 효과를 효율적으로 증진시킬 수 있어서, 인류의 건강증진과 보건의료 등 관련산업의 발전에도 큰 일익을 담당할 것이다. The combination preparation provided by the present invention can efficiently improve the prevention or treatment effect of the above diseases even when administered in low doses without using conventional expensive drugs, thereby contributing to the promotion of human health and the development of related industries such as health care. It will play a big role.
도 1은 사람 SH-SY5Y 세포에 메트포르민, 콜치신 단독 시약처리 또는 메트포르민/콜치신 병용 시약처리하였을 때에 나타나는 샤페론 단백질 HSPB8 mRNA 발현 (A-C) 또는 단백질 발현 (D)을 정량화한 것이다.
도 2는 H2O2 처리된 사람 SH-SY5Y 세포에 메트포르민, 콜치신 단독 시약처리 또는 메트포르민/콜치신 병용시약으로 처리하였을 때에 나타나는 TDP-43의 응집을 TDP-43 응집 키트 (Aggregation kit)를 사용하여 정량화한 것이다.
도 3은 H2O2 처리된 사람 SH-SY5Y 세포에 메트포르민과 콜치신의 단독 시약처리 또는 메트포르민/콜치신의 병용 시약처리하였을 때에 TDP-43의 응집정도를 면역형광염색법 및 형광현미경을 통해 관찰한 결과를 제시한 것 (A)이고, 측정된 stress granules을 정량화한 것 (B)이다. 또한, Filter retardation 분석법을 통해 TDP-43의 응집정도를 확인 및 정량화한 것 (C)을 나타낸 것이다.
도 4는 사람 GFP-TDP-25가 형질주입된 SH-SY5Y 세포에 메트포르민과 콜치신의 단독 시약처리 또는 메트포르민/콜치신의 병용 시약처리하였을 때에, TDP-25의 세포 내 위치를 형광현미경으로 관찰한 것 (A)을 제시하였고, 불용성 TDP-43 및 용해성 TDP-43 단백질의 발현 (B)을 관찰하여 TDP-43의 응집정도를 정량화 (C)한 것이다. 도 4에서 파란색 형광은 DAPI로써 핵을 나타내는 것이고, 초록색 형광은 GFP로써 TDP-25를 나타낸다.
도 5는 사람 SH-SY5Y 세포에 메트포르민과 콜치신의 단독 시약처리 또는 메트포르민/콜치신의 병용 시약처리하였을 때에 나타나는 오토파지 전사인자 TFEB mRNA 발현을 정량화한 것이다.
도 6은 사람 SH-SY5Y 세포에 메트포르민과 콜치신의 단독 시약처리 또는 메트포르민/콜치신의 병용 시약처리하였을 때에 나타나는 오토파지 수용체 SQSTM1/p62 mRNA 발현을 정량화한 것이다.
도 7은 사람 SH-SY5Y 세포에 메트포르민과 콜치신의 단독 시약처리 또는 메트포르민/콜치신의 병용 시약처리하였을 때에 나타나는 오토파지 마커 MAP1LC3A mRNA 발현을 정량화한 것이다.
도 8은 사람 SH-SY5Y 세포에 메트포르민과 콜치신의 단독 시약처리 또는 메트포르민/콜치신의 병용 시약처리하였을 때에 나타나는 p62 단백질 발현을 정량화한 것이다.
도 9는 사람 SH-SY5Y 세포에 메트포르민과 콜치신의 단독 시약처리 또는 메트포르민/콜치신의 병용 시약처리하였을 때에 나타나는 LC3-II 단백질 발현을 정량화한 것이다.
Figure 1 quantifies the chaperone protein HSPB8 mRNA expression (AC) or protein expression (D) when human SH-SY5Y cells are treated with metformin or colchicine alone or with a metformin/colchicine combination reagent.
Figure 2 shows the aggregation of TDP-43 that appears when human SH-SY5Y cells treated with H 2 O 2 are treated with metformin or colchicine alone or with a metformin/colchicine combination reagent using a TDP-43 aggregation kit. It was quantified using
Figure 3 shows the degree of TDP-43 aggregation observed through immunofluorescence staining and fluorescence microscopy when human SH-SY5Y cells treated with H 2 O 2 were treated with metformin and colchicine alone or with a combination of metformin and colchicine. One result is presented (A), and the measured stress granules are quantified (B). In addition, the degree of aggregation of TDP-43 was confirmed and quantified through filter retardation analysis (C).
Figure 4 shows the intracellular location of TDP-25 observed under a fluorescence microscope when SH-SY5Y cells transfected with human GFP-TDP-25 were treated with metformin and colchicine alone or with a combination of metformin and colchicine. (A) was presented, and the degree of aggregation of TDP-43 was quantified (C) by observing the expression of insoluble TDP-43 and soluble TDP-43 proteins (B). In Figure 4, blue fluorescence represents the nucleus as DAPI, and green fluorescence represents TDP-25 as GFP.
Figure 5 quantifies the expression of autophagy transcription factor TFEB mRNA when human SH-SY5Y cells are treated with metformin and colchicine alone or with a combination of metformin and colchicine.
Figure 6 quantifies the autophagy receptor SQSTM1/p62 mRNA expression when human SH-SY5Y cells are treated with metformin and colchicine alone or with a combination of metformin and colchicine.
Figure 7 quantifies the expression of the autophagy marker MAP1LC3A mRNA when human SH-SY5Y cells are treated with metformin and colchicine alone or with a combination of metformin and colchicine.
Figure 8 quantifies p62 protein expression when human SH-SY5Y cells are treated with metformin and colchicine alone or with a combination of metformin and colchicine.
Figure 9 quantifies LC3-II protein expression when human SH-SY5Y cells are treated with metformin and colchicine alone or with a combination of metformin and colchicine.
본 발명에서 제공하는 콜치신 또는 이의 약학적으로 허용 가능한 염 및 메트포르민 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하여 형성되는 복합제를 사람 SH-SY5Y 세포에 투여하는 경우, TDP-43의 응집정도가 저하되는 것을 확인하고 이에 기초하여 본 발명을 완성하게 되었다.When the complex agent comprising colchicine or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof provided by the present invention as active ingredients is administered to human SH-SY5Y cells, aggregation of TDP-43 occurs. It was confirmed that the degree was decreasing, and based on this, the present invention was completed.
이하 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.
본 발명에서 사용되는 주요 유효성분인 콜치신 (Colchicine)은 콜키쿰(Colchicum) 속 식물에서 추출된 물질로서 비스테로이드성 항염증제가 통풍에 대한 치료효과가 원활히 나타나지 않을 때 통풍에 대한 대체적 약물로써 주로 사용되는 약물이고, 가족성 지중해열, 심낭염, 베체트병 등의 치료에도 사용된다. Colchicine, the main active ingredient used in the present invention, is a substance extracted from plants of the genus Colchicum and is mainly used as an alternative drug for gout when non-steroidal anti-inflammatory drugs do not have a smooth treatment effect on gout. This drug is also used to treat familial Mediterranean fever, pericarditis, and Behcet's disease.
본 발명에서 사용되는 또 다른 유효성분인 메트포르민 (Metformin)은 바이구아니드계 (Biguanide) 약물로서 혈당 개선 효과가 있어서 주로 당뇨병 치료제로 사용되는 약물이다. 메트포르민의 작용기전은 정확하지는 않으나 미토콘드리아에서 일어나는 세포호흡을 억제하고 AMPK를 활성화시켜 글루카곤에 의해 유도되는 cAMP의 농도 상승을 막아 결과적으로 PKA의 활성을 억제하여 포도당의 생성을 억제한다고 알려져 있다.Metformin, another active ingredient used in the present invention, is a biguanide drug and is mainly used as a treatment for diabetes due to its blood sugar improving effect. Although the exact mechanism of action of metformin is not known, it is known to inhibit cellular respiration that occurs in mitochondria and activate AMPK to prevent the increase in cAMP concentration induced by glucagon, which ultimately inhibits the activity of PKA and thus inhibits glucose production.
본 발명에서 서술하는 TDP-43 단백질의 발현과 관련되는 질환은 전측두엽 치매 (FTD, 예컨대 산발성 또는 가족성의 운동-뉴런 질환 (MND)이 있거나 없는 것, 프로그래뉼린 (GRN) 돌연변이가 있는 것, C9orf72 돌연변이가 있는 것, TARDBP 돌연변이가 있는 것, 발로신-함유 단백질 (VCP)의 돌연변이가 있는 것, 염색체 9p에 연결되어 있는 것, 피질기저 퇴행, 유비퀴틴-양성 TDP-43 봉입체 (FTLDTDP)가 있는 전측두엽 퇴행 (FTLD), 호은성 입자 질병, 픽병, 의미형 변이체 원발 진행성 실어증 (svPPA), 행동변이 FTD (bvFTD), 비유창 변이 원발 진행성 실어증(nfvPPA) 등), 근위축성 측삭 경화증 (ALS, 예컨대 산발성 ALS, TARDBP 돌연변이가 있는 것, 안지오제닌 (ANG) 돌연변이가 있는 것), 알렉산더병 (AxD), 변연계-우세 연령-관련 TDP-43 뇌병증 (LATE), 만성 외상성 뇌병증, 페리 증후군, 알츠하이머병 (AD, AD의 산발성 및 가족성 형태포함), 다운 증후군, 영국 가족성 치매, 폴리글루타민 질환 (헌팅턴병 및 척수소뇌 실조 유형 3 (SCA3; 마카도 조셉병으로도 공지됨)), 해마 경화증 치매 및 근병증 (산발성 봉입체 근염, 발로신-함유 단백질 (VCP)에 돌연변이가 있는 봉입체 근염; 또한 골의 파제트병 및 전측두엽 치매), 테두리 액포가 있는 눈인두 근이영양증, 미오틸린 (MYOT) 유전자의 돌연변이 또는 데스민 (DES)을 코딩하는 유전자의 돌연변이가 있는 근섬유 근병증, 외상성 뇌손상 (TBI), 루이소체가 있는 치매 (DLB) 또는 파킨슨병 (PD) 등을 의미한다.Diseases associated with the expression of the TDP-43 protein described in the present invention include frontotemporal dementia (FTD, with or without sporadic or familial motor-neuron disease (MND), with progranulin (GRN) mutations, Those with C9orf72 mutations, those with TARDBP mutations, those with mutations in valosin-containing protein (VCP), those linked to chromosome 9p, those with corticobasal degeneration, and those with ubiquitin-positive TDP-43 inclusion bodies (FTLDTDP). Frontotemporal lobe degeneration (FTLD), fluent particle disease, Pick's disease, semantic variant primary progressive aphasia (svPPA), behavioral variant FTD (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), etc.), amyotrophic lateral sclerosis (ALS, (e.g. sporadic ALS, those with TARDBP mutations, those with angiogenin (ANG) mutations), Alexander disease (AxD), limbic-dominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, and Alzheimer's diseases (AD, including sporadic and familial forms of AD), Down syndrome, British familial dementia, polyglutamine disorders (Huntington's disease and spinocerebellar ataxia type 3 (SCA3; also known as Machado-Joseph disease)), hippocampal sclerosis dementia and myopathies (sporadic inclusion body myositis, inclusion body myositis with mutations in valosin-containing protein (VCP); also Paget's disease of bone and frontotemporal dementia), oculopharyngeal muscular dystrophy with border vacuoles, mutations in the myotilin (MYOT) gene. or myofibrillar myopathy, traumatic brain injury (TBI), dementia with Lewy bodies (DLB), or Parkinson's disease (PD) with mutations in the gene encoding desmin (DES).
본 발명의 발명자들은 콜치신과 메트포르민을 병용 형태로 시약 처리하는 경우에 TDP-43 단백질의 비정상적 응집이 저하된다는 것을 다양한 실험을 통하여 확인하였다.The inventors of the present invention confirmed through various experiments that abnormal aggregation of TDP-43 protein is reduced when treated with a combination of colchicine and metformin.
본 발명의 일 실시예에서는 사람의 신경모세포종 세포주인 SH-SY5Y 세포에 콜치신 단독투여, 메트포르민 단독투여 또는 콜치신과 메트포르민을 병용 투여하였을 경우 TDP-43 단백질의 응집억제량을 각각 비교하였을 때, 콜치신과 메트포르민을 병용 투여하였을 경우에 상기 단백질의 응집 저하가 가장 크게 나타났다.In one embodiment of the present invention, when comparing the amount of inhibition of aggregation of TDP-43 protein when colchicine alone, metformin alone, or colchicine and metformin were administered in combination to SH-SY5Y cells, a human neuroblastoma cell line, When colchicine and metformin were administered together, the greatest decrease in aggregation of the above proteins was observed.
또한, 본 발명의 일 실시예에서는 상기의 세포주에 콜치신과 메트포르민을 병용 투여했을 때, 상기 약물을 단독 투여했을 때보다 산화 스트레스에 의해 유도된 TDP-43의 비정상적 응집을 훨씬 더 억제하는 것으로 나타났다.In addition, in one embodiment of the present invention, when colchicine and metformin were administered in combination to the above cell line, it was shown to inhibit abnormal aggregation of TDP-43 induced by oxidative stress to a greater extent than when the drugs were administered alone. .
또한, 본 발명의 일 실시예에서는 TDP-43 응집-세포모델에서 콜치신과 메트포르민을 병용 투여했을 때, 상기 약물을 단독 투여했을 때보다 TDP-43의 응집을 현저히 억제하는 결과를 보였고, 상기의 결과는 콜치신과 메트포르민을 병용 투여했을 때에 세포의 자가포식 (Autophagy) 마커 유전자 및 샤페론 (Chaperone) 단백질의 발현을 증가시킴으로써 TDP-43의 비정상적 응집을 억제하는 것으로 나타났다.In addition, in one embodiment of the present invention, when colchicine and metformin were administered together in a TDP-43 aggregation-cell model, the results showed that the aggregation of TDP-43 was significantly inhibited compared to when the drugs were administered alone, as described above. The results showed that the combined administration of colchicine and metformin suppressed the abnormal aggregation of TDP-43 by increasing the expression of cell autophagy marker genes and chaperone proteins.
상기와 같은 결과로부터 본 발명에서 제공하는 약학 조성물은 TDP-43 단백질의 비정상적인 응집 또는 TDP-43 단백질의 잘못된 위치화 (Mislocalization)에 의한 세포질에서의 축적으로 매개되는 질환에서, 샤페론 유전자의 발현을 증가시키고, 또한, 자가포식 유전자의 발현을 증가시키며, TDP-43 단백질의 비정상적 응집 및 잘못된 위치화를 억제하는 것을 확인하였고, 이를 통해서 본 발명자들은 본 발명을 완성하게 되었다.From the above results, the pharmaceutical composition provided by the present invention increases the expression of chaperone genes in diseases mediated by abnormal aggregation of TDP-43 protein or accumulation in the cytoplasm due to mislocalization of TDP-43 protein. In addition, it was confirmed that it increases the expression of autophagy genes and suppresses abnormal aggregation and mislocalization of TDP-43 protein, through which the present inventors completed the present invention.
본 발명에서 사용되는 상이 용어인 '복합제제'라는 것은 본 발명에서 제공하는 약학 조성물을 의미한다.The term 'combined preparation' used in the present invention refers to the pharmaceutical composition provided by the present invention.
본 발명의 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다. 또한, 통상의 방법에 따라 산제, 환제, 과립제, 정제, 캡슐제, 내용액제, 유제, 현탁액, 에멀젼, 시럽, 에어로졸, 외용제, 멸균된 수용액, 비수성용제, 동결건조제제, 좌제 및 멸균 주사제의 형태로 제형화하여 사용될 수 있으며, 바람직하게는 경구투여에 적합한 단위투여형의 제제로 제형화시켜 사용될 수 있다.The composition of the present invention may further include appropriate carriers, excipients, and diluents commonly used in the preparation of pharmaceutical compositions. In addition, in the form of powders, pills, granules, tablets, capsules, internal solutions, emulsions, suspensions, emulsions, syrups, aerosols, topical preparations, sterilized aqueous solutions, non-aqueous solutions, freeze-dried preparations, suppositories and sterilized injections according to conventional methods. It can be formulated and used, and preferably can be formulated and used as a unit dosage preparation suitable for oral administration.
본 발명에 따른 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서, ‘약학적으로 유효한 양'은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명에 따른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 통상의 기술자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, 'pharmaceutically effective amount' refers to an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type, severity, and activity of the patient's disease. , can be determined based on factors including sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, drugs used simultaneously, and other factors well known in the field of medicine. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects, and this can be easily determined by a person skilled in the art.
본 발명의 약학적 조성물은 개체에게 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 복강, 피하, 비내, 경피, 자궁 내 경막 또는 뇌혈관 내 주사에 의해 투여될 수 있다. 본 발명의 약학적 조성물은 치료할 질환, 투여 경로, 환자의 연령, 성별 및 체중 및 질환의 중등도 등의 여러 관련 인자와 함께, 활성성분인 약물의 종류에 따라 결정된다.The pharmaceutical composition of the present invention can be administered to an individual through various routes. All modes of administration are contemplated, for example, oral, rectal or by intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, transdermal, intrathecal or intracerebrovascular injection. The pharmaceutical composition of the present invention is determined depending on the type of drug that is the active ingredient, along with various related factors such as the disease to be treated, the route of administration, the patient's age, gender and weight, and the severity of the disease.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Below, preferred embodiments are presented to aid understanding of the present invention. However, the following examples are provided only to make the present invention easier to understand, and the content of the present invention is not limited by the following examples.
실시예 1Example 1
메트포르민과 콜치신의 병용처리가 샤페론 단백질 HSPB8의 발현증가에 시너지 효과를 나타내는지의 여부Whether the combined treatment of metformin and colchicine has a synergistic effect in increasing the expression of the chaperone protein HSPB8.
사람의 신경모세포종 세포주인 SH-SY5Y 세포에 메트포르민 (0, 0.1, 0.5, 1, 2, 5 mM) 또는 콜치신 (0, 1, 10, 100, 500, 1000 nM)을 각 농도별로 시약처리하고 24시간 후, 샤페론 단백질 HSPB8 (Heat Shock Protein Family B (Small) Member 8)의 mRNA 발현을 관찰하고, 그 결과를 도 1에 제시하였다. SH-SY5Y cells, a human neuroblastoma cell line, were treated with metformin (0, 0.1, 0.5, 1, 2, 5 mM) or colchicine (0, 1, 10, 100, 500, 1000 nM) at each concentration. After 24 hours, mRNA expression of the chaperone protein HSPB8 (Heat Shock Protein Family B (Small) Member 8) was observed, and the results are shown in Figure 1.
메트포르민 또는 콜치신 단독 시약처리에 의해 HSPB8의 mRNA 발현이 2배 정도 증가한 것과 비교하여, 메트포르민 (5 mM)과 콜치신 (10, 100, 500, 1000 nM)의 병용 시약처리 시에는 HSPB8의 mRNA 발현이 콜치신의 농도 의존적으로 20배 이상 증가시키는 것을 관찰할 수 있었다 (도 1A-1C). Compared to the two-fold increase in the mRNA expression of HSPB8 when treated with metformin or colchicine alone, the mRNA expression of HSPB8 increased when treated with a combination of metformin (5 mM) and colchicine (10, 100, 500, 1000 nM). It was observed that colchicine increased more than 20-fold in a concentration-dependent manner (Figures 1A-1C).
HSPB8의 mRNA 발현에 메트포르민 및 콜치신 병용처리가 상가작용이 있음을 확있하였으므로 메트포르민 (5 mM) 및 콜치신 (1000 nM) 농도를 고정하여 HSPB8 단백질 발현을 관찰하였다. 이때 HSPB8의 단백질 발현은 메트포르민 또는 콜치신의 단독 시약처리에 의해서는 미비한 변화를 보였으나, 메트포르민 및 콜치신의 병용처리에 의해서는 8배 정도 증가하는 상가작용이 있음을 확인하였다 (도 1D, 각 도면에서 **P<0.01, *P<0.05는 정상세포군과 비교; ##P<0.01는 콜치신 단독군과 비교한 것이다).Since it was confirmed that the combined treatment of metformin and colchicine had an additive effect on the mRNA expression of HSPB8, HSPB8 protein expression was observed by fixing the concentrations of metformin (5 mM) and colchicine (1000 nM). At this time, protein expression of HSPB8 showed a slight change when treated with metformin or colchicine alone, but it was confirmed that there was an additive effect of about 8-fold increase by combined treatment with metformin and colchicine (Figure 1D, each In the figure, ** P < 0.01, * P < 0.05 compared to the normal cell group; ## P < 0.01 compared to the colchicine only group).
실시예 2Example 2
메트포르민과 콜치신의 병용처리가 산화 스트레스에 의해 유도된 TDP-43의 비정상적 응집을 억제하는지의 여부Whether the combined treatment of metformin and colchicine inhibits abnormal aggregation of TDP-43 induced by oxidative stress.
사람의 신경모세포종 세포주인 SH-SY5Y 세포에 메트포르민 (0, 0.1, 0.5, 1, 2, 5 mM) 또는 콜치신 (0, 1, 10, 100, 500, 1000 nM)을 각 농도별로 시약처리하고 24시간 후, 산화 스트레스를 유도하기 위해, 1 mM 과산화수소 (H2O2)를 1시간 동안 시약처리하였다. SH-SY5Y cells, a human neuroblastoma cell line, were treated with metformin (0, 0.1, 0.5, 1, 2, 5 mM) or colchicine (0, 1, 10, 100, 500, 1000 nM) at each concentration. After 24 hours, to induce oxidative stress, 1 mM hydrogen peroxide (H 2 O 2 ) was treated for 1 hour.
이후, 각 샘플에서의 TDP-43의 응집 정도를 측정한 결과, 1 mM 과산화수소 (H2O2)는 TDP-43의 비정상적 응집을 상당히 유도하였고, 메트포르민 단독처리는 과산화수소에 의해 유도된 TDP-43 응집에 유의한 효과를 가지지 못하는 것을 관찰하였으며 (도 2A), 콜치신 단독처리도 이에 미미한 효과를 나타내는 것을 확인하였다(도 2B). Afterwards, as a result of measuring the degree of aggregation of TDP-43 in each sample, 1 mM hydrogen peroxide (H 2 O 2 ) significantly induced abnormal aggregation of TDP-43, and treatment with metformin alone reduced TDP-43 induced by hydrogen peroxide. It was observed that it had no significant effect on aggregation (Figure 2A), and it was confirmed that treatment with colchicine alone also had a minor effect (Figure 2B).
하지만, 메트포르민 및 콜치신의 병용 시약처리 시에는 상기 약물의 단독 시약처리와 비교하여 과산화수소에 의해 유도된 TDP-43 응집이 상당히 억제된다는 것을 확인하였고, 콜치신 최고농도 (1000 nM)와 메트포르민이 병용처리된 군에서는 거의 정상 세포 수준으로 억제되는 것을 관찰하였다 (도 2C). However, it was confirmed that the combined reagent treatment of metformin and colchicine significantly inhibited TDP-43 aggregation induced by hydrogen peroxide compared to the single reagent treatment of the drug, and the highest concentration of colchicine (1000 nM) was used in combination with metformin. In the treated group, inhibition was observed to almost normal cell levels (Figure 2C).
도 2에 제시된 상기의 결과를 현미경 및 세포 단백질을 이용하여 다시 한번 확인하였다 (도 3). 과산화수소 (H2O2)는 세포질에서 TDP-43 응집을 상당히 유도하였고, 메트포르민 또는 콜치신의 단독처리는 세포질에서의 TDP-43 응집을 억제하지 못하였으나, 메트포르민과 콜치신의 병용 시약처리는 정상세포의 수준으로 TDP-43의 응집을 억제시킨다는 것을 확인하였다 (도 3A, 3B). 이 결과는 도 3C의 Filter Retardation assay 실험에서 다시 한번 확인할 수 있었다 (상기 도면에서 **P<0.01는 정상세포군과 비교; ##P<0.01, #P<0.05는 과산화수소군과 비교; $$P<0.01, $P<0.05는 과산화수소+콜치신 단독군과 비교한 것이다).The above results shown in Figure 2 were confirmed once again using a microscope and cell proteins (Figure 3). Hydrogen peroxide (H 2 O 2 ) significantly induced TDP-43 aggregation in the cytoplasm, and treatment with metformin or colchicine alone did not inhibit TDP-43 aggregation in the cytoplasm, but treatment with a combination of metformin and colchicine was normal. It was confirmed that it inhibits the aggregation of TDP-43 at the cellular level (Figures 3A, 3B). This result was confirmed once again in the Filter Retardation assay experiment in Figure 3C (in the figure, ** P < 0.01 compared to the normal cell group; ## P < 0.01, # P < 0.05 compared to the hydrogen peroxide group; $$ P <0.01, $ P<0.05 compared to the hydrogen peroxide + colchicine group alone).
실시예 3Example 3
메트포르민과 콜치신의 병용처리가 TDP-43 응집-세포모델에서 TDP-43의 응집을 억제하는지의 여부Whether the combined treatment of metformin and colchicine inhibits TDP-43 aggregation in a TDP-43 aggregation-cell model.
사람의 신경모세포종 세포주인 SH-SY5Y 세포에서 TDP-43 단백질의 응집 모델을 구축하기 위해 GFP-TDP-25 플라스미드를 세포 내에 형질 주입시켰고, 상기 형질 주입된 GFP-TDP-25 (GFP: green fluorescent protein)는 세포질에 존재하는 것을 확인할 수 있다. To construct an aggregation model of the TDP-43 protein in SH-SY5Y cells, a human neuroblastoma cell line, GFP-TDP-25 plasmid was transfected into the cells, and the transfected GFP-TDP-25 (GFP: green fluorescent protein) was transfected into the cells. ) can be confirmed to exist in the cytoplasm.
상기 세포의 메트포르민 또는 콜치신의 단독 처리시에는 비정상적으로 세포질에 존재하는 TDP-25에 영향을 미치지 않았지만, 메트포르민과 콜치신의 병용 시약처리는 세포질에 존재하는 TDP-25의 위치를 핵 내로 변화시킨다는 것을 확인하였다 (도 4A). Treatment of the cells with metformin or colchicine alone did not affect TDP-25 abnormally present in the cytoplasm, but combined treatment with metformin and colchicine changed the location of TDP-25 present in the cytoplasm into the nucleus. This was confirmed (Figure 4A).
또한, GFP-TDP-25 플라스미드를 이용한 TDP-43 응집 모델에서 메트포르민 (5 mM) 또는 콜치신 (1000 nM)의 단독처리는 불용성 TDP-43의 발현을 미미하게 감소시켰으나, 메트포르민과 콜치신의 병용 시약처리는 불용성 TDP-43 발현을 상당히 감소시키는 것을 확인하였다 (도 4B, 4C, 상기 도면에서 **P<0.01, *P<0.05는 정상세포군과 비교; ##P<0.01는 콜치신 단독군과 비교한 것이다). Additionally, in the TDP-43 aggregation model using the GFP-TDP-25 plasmid, treatment with metformin (5 mM) or colchicine (1000 nM) alone slightly reduced the expression of insoluble TDP-43, but combined use of metformin and colchicine It was confirmed that the reagent treatment significantly reduced the expression of insoluble TDP-43 (Figures 4B, 4C, ** P < 0.01, * P < 0.05 compared to the normal cell group; ## P < 0.01 compared to the colchicine only group) compared to ).
실시예 4Example 4
메트포르민과 콜치신의 병용처리가 세포의 자가면역 증가에 시너지 효과를 나타내는지의 여부Whether the combined treatment of metformin and colchicine has a synergistic effect in increasing cellular autoimmunity
사람의 신경모세포종 세포주인 SH-SY5Y 세포에 메트포르민 (0, 0.1, 0.5, 1, 2, 5 mM) 또는 콜치신 (0, 1, 10, 100, 500, 1000 nM)을 각 농도별로 시약처리하고 24시간 후, 오토파지 마스터 전사인자인 TFEB (도 5), 오토파지 수용체인 SQSTM1/p62 (도 6) 및 오토파지 마커 MAP1LC3A (도 7)의 mRNA 발현을 관찰하였다. SH-SY5Y cells, a human neuroblastoma cell line, were treated with metformin (0, 0.1, 0.5, 1, 2, 5 mM) or colchicine (0, 1, 10, 100, 500, 1000 nM) at each concentration. After 24 hours, the mRNA expression of the autophagy master transcription factor TFEB (Figure 5), the autophagy receptor SQSTM1/p62 (Figure 6), and the autophagy marker MAP1LC3A (Figure 7) were observed.
TFEB, SQSTM1/p62 및 MAP1LC3A 유전자의 mRNA 발현 변화에 있어서, 메트포르민의 단독 시약처리는 전혀 효과를 나타내지 않았고, 콜치신의 단독 시약처리는 약 2 내지 3배의 증가 효과를 나타내는 것을 확인하였다. 이와 비교하여 메트포르민 (5 mM)과 콜치신 (10, 100, 500, 1000 nM)의 병용 시약처리는 상기 유전자들의 발현에 있어서 10배 이상의 상가효과를 가지는 것을 관찰할 수 있었다 (도 5, 6, 7). In terms of changes in mRNA expression of TFEB, SQSTM1/p62, and MAP1LC3A genes, treatment with metformin alone did not show any effect, and treatment with colchicine alone showed an increase effect of about 2 to 3 times. In comparison, it was observed that the combined reagent treatment of metformin (5 mM) and colchicine (10, 100, 500, 1000 nM) had an additive effect of more than 10 times on the expression of the above genes (Figures 5 and 6, 7).
또한, TDP-43 응집 모델에서 메트포르민과 콜치신이 자가면역에 미치는 영향을 확인하기 위해, GFP-TDP-25 플라스미드가 형질주입된 SH-SY5Y 세포에 메트포르민 (5 mM)과 콜치신 (1000 nM)을 단독 또는 병용 시약처리 하였다. 상기 시약처리에 의해서 증가한 p62의 단백질 발현은 메트포르민 또는 콜치신의 단독 시약처리와 비교하여 메트포르민과 콜치신의 병용 시약처리에 의해 상당히 억제된 것을 확인하였다 (도 8). 또한, LC3-II 발현은 메트포르민 또는 콜치신의 단독 시약처리와 비교하여 메트포르민과 콜치신의 병용 시약처리에 의해 유의하게 증가한 것을 확인하였다(도 9, 도면에서 **P<0.01, *P<0.05는 정상세포군과 비교; ##P<0.01, #P<0.05는 콜치신 단독군과 비교한 것이다). Additionally, to confirm the effect of metformin and colchicine on autoimmunity in the TDP-43 aggregation model, metformin (5 mM) and colchicine (1000 nM) were added to SH-SY5Y cells transfected with GFP-TDP-25 plasmid. were treated with reagents alone or in combination. It was confirmed that the protein expression of p62 increased by the reagent treatment was significantly suppressed by the combined reagent treatment of metformin and colchicine compared to the single reagent treatment of metformin or colchicine (FIG. 8). In addition, LC3-II expression was confirmed to be significantly increased by combined treatment with metformin and colchicine compared to treatment with metformin or colchicine alone (Figure 9, ** P < 0.01, * P < 0.05 in the figure. is compared to the normal cell group; ## P<0.01, # P<0.05 is compared to the colchicine only group).
상기의 결과로부터 알 수 있듯이, TDP-43 단백질의 비정상적 응집은 메트포르민 또는 콜치신의 단독 시약처리에 의해서는 거의 저하되지 않았으나, 콜치신과 메트포르민의 병용투여에 의해서는 상기 단백질의 응집억제 효과가 유의적으로 나타나는데, 이는 상기 두 가지 약물이 명백한 시너지 효과를 나타내어 루게릭병 등 근위축성 측삭 경화증 등을 효율적으로 예방 내지는 치료할 수 있다는 것을 의미한다.As can be seen from the above results, the abnormal aggregation of TDP-43 protein was hardly reduced by treatment with metformin or colchicine alone, but the co-administration of colchicine and metformin showed a significant effect of inhibiting the aggregation of the protein. This means that the two drugs have a clear synergistic effect and can effectively prevent or treat amyotrophic lateral sclerosis such as Lou Gehrig's disease.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.The description of the present invention described above is for illustrative purposes, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. will be. Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive.
본 발명은 산업상이용가능하다.The present invention is applicable industrially.
Claims (7)
A pharmaceutical composition for preventing or treating a degenerative nervous system disease, wherein the pharmaceutical composition comprises colchicine or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof. Pharmaceutical composition for prevention or treatment of
The method of claim 1, wherein the degenerative nervous system disease is a disease mediated by abnormal aggregation of TDP-43 protein or accumulation in the cytoplasm due to mislocalization of TDP-43 protein. Pharmaceutical compositions for prevention or treatment
The method of claim 2, wherein the disease mediated by abnormal aggregation of the TDP-43 protein or accumulation in the cytoplasm by mislocalization of the TDP-43 protein is frontotemporal dementia, amyotrophic lateral sclerosis, Alexander's disease, Affinity particle disease, ALS in Guam Parkinsonism-dementia complex, limbic-dominant age-related TDP-43 encephalopathy, chronic traumatic encephalopathy, Perry syndrome, Alzheimer's disease, Down syndrome, UK familial dementia, Huntington's disease, Machado Joseph's disease, hippocampus For the prevention or treatment of a degenerative nervous system disease characterized in that it is selected from the group consisting of sclerotic dementia, inclusion body myositis, oculopharyngeal muscular dystrophy with border vacuoles, myofibrillar myopathy, traumatic brain injury, dementia with Lewy bodies, and Parkinson's disease. pharmaceutical composition
The method of claim 1, wherein the pharmaceutical composition increases chaperone gene expression and autophagy in diseases mediated by abnormal aggregation of TDP-43 protein or accumulation in the cytoplasm due to mislocalization of TDP-43 protein. A pharmaceutical composition for the prevention or treatment of degenerative nervous system diseases, characterized by increasing gene expression and inhibiting abnormal aggregation and mislocalization of TDP-43 protein.
The method of claim 1, wherein the pharmaceutical composition is formulated in the form of any one agent selected from oral, rectal, intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, intrauterine, intracerebrovascular, and transdermal administration. Pharmaceutical composition for preventing or treating degenerative nervous system diseases, characterized in that
The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition includes powders, pills, granules, tablets, capsules, oral solutions, emulsions, suspensions, emulsions, syrups, aerosols, topical preparations, sterilized aqueous solutions, non-aqueous solutions, freeze-dried preparations, suppositories, and sterile preparations. A pharmaceutical composition for the prevention or treatment of degenerative nervous system diseases, characterized in that it is prepared in any one formulation selected from the group consisting of injections.
The method of claim 1, wherein the pharmaceutical composition is selected from the group consisting of melatonin, creatine, magnesium, coenzyme Q10, vitamin D, vitamin B, vitamin E, L-serine, L-Carnitine, and N-acetylcysteine. A pharmaceutical composition for the prevention or treatment of degenerative nervous system diseases, characterized in that it further comprises one or more ingredients
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| US20120023352A1 (en) | 2008-11-24 | 2012-01-26 | Icera Inc. | Active power management |
| US20220120906A1 (en) | 2019-05-13 | 2022-04-21 | Ouster, Inc. | Synchronized image capturing for electronic scanning lidar systems |
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