KR101504000B1 - Marker for diagnosing neurodegenerative diseases and its use - Google Patents
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Abstract
본원은 콜레스테롤 수산화 유도체의 혈청내 수준을 측정하기 위하여 콜레스테롤 수산화 유도체를 검출하는 물질을 포함하는 퇴행성 신경질환의 진단용 조성물 및 이를 포함하는 진단용 키트, 퇴행성 신경질환 진단용 정보 제공 방법에 관한 것이다. 콜레스테롤 수산화 유도체는 퇴행성 신경질환 환자의 시료에서 유의적으로 감소되어 혈액에서 퇴행성 신경질환의 발병여부 및 중증도를 간편한 방법으로 효과적이며 재현성있게 진단하는 것이 가능하다.The present invention relates to a composition for diagnosing a degenerative neurological disease comprising a substance for detecting a cholesterol hydroxyl derivative to measure serum levels of a cholesterol hydroxylated derivative, a diagnostic kit comprising the same, and a method for providing information for diagnosing degenerative neurological diseases. Cholesterol hydroxylated derivatives are significantly reduced in samples of patients with degenerative neurological diseases, and it is possible to diagnose the extent and severity of degenerative neurologic diseases in the blood in an effective and reproducible manner by a simple method.
Description
본원은 퇴행성 신경질환을 진단할 수 있는 조성물에 관한 것이다.
The present invention relates to a composition capable of diagnosing degenerative neurological diseases.
콜레스테롤은 중추신경계의 주요 구성 성분일 뿐 아니라 신호 전달, 신경계 형성, 및 신경퇴행에 관여하는 것으로 알려져 있다. 인간의 대뇌 무게는 전체 체중의 약 2%를 차지하지만 대뇌 콜레스테롤의 양은 인체내 콜레스테롤의 25%에 달하는 것으로 알려져 있으며, 중추신경계조직의 80% 이상은 지질로 이루어져있다. 이러한 중추신경계의 대부분을 구성하는 콜레스테롤의 기능은 이온채널의 투과도(ion channel permeability)조절, 신호 전달, 신경세포연접부 형성(synaptogenesis), 신경연접소포역동(synaptic vesicle dynamics), 신경재생 및 퇴행(regeneration and degeneration)에 관여할 것으로 추정되고 있다. Cholesterol is not only a major component of the central nervous system but is also known to be involved in signal transduction, nervous system formation, and neurodegeneration. Human cerebral weight accounts for about 2% of total body weight, but cereal cholesterol is known to account for 25% of the cholesterol in the human body, and more than 80% of the central nervous system tissue is composed of lipid. The function of cholesterol, which constitutes most of the central nervous system, is controlled by ion channel permeability regulation, signal transduction, synaptogenesis, synaptic vesicle dynamics, nerve regeneration and regression regeneration and degeneration.
한편, 퇴행성 신경질환은 알츠하이머, 파킨슨, 근위축성 측삭경화증이 대표적이며, 다른 질환에 비하여 치료제가 없고, 아직 그 명확한 발병기전도 규명되지 않고 있다. 특히, 루게릭병이라고도 불리는 근위축성측삭경화증(ALS: amyotrophic lateral sclerosis)은 뇌간과 척수에 있는 하운동신경원세포와 함께 대뇌피질과 상운동신경계를 침범하여 생기는 퇴행성 신경질환으로서, 근육운동을 조절하는 뉴런 안에 단백질 덩어리들이 축적되어 운동신경을 침범하여 그 신경에 의해 지배되는 근육이 약해지고 위축되어 사망에 이르게 되는 치명적인 퇴행성 신경질환이다. On the other hand, neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis are representative, and there is no therapeutic agent compared with other diseases, and the clear mechanism of the disease has not been clarified yet. Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a neurodegenerative disease caused by invasion of the cerebral cortex and upper motor nervous system along with lower motor neurons in the brain stem and spinal cord, It is a fatal neurodegenerative disease that accumulates protein masses inside the nerves to invade the motor nerves and weaken the muscles dominated by the nerves and lead to atrophy and death.
근위축성측삭경화증은 일반적으로 신경 근육 장애로 간주되었지만, 지금은 멀티 시스템 신경 질환으로 인식되고 있다. 근위축성측삭경화증은 일반적으로 빠르게 진행되며, 진단 후 2 내지 5 년 이내에 호흡 곤란을 포함하는 총체적인 마비가 진행되어 사망에 이르게 된다. 근위축성측삭경화증의 연간 발생률은 10 만 명당 1-2명이며, 가족력으로 오는 근위축성측삭경화증 약 10% 정도이다. 가족성 근위축성측삭경화증을 제외하고는 아직 원인이 밝혀져 있지 않다.Amyotrophic lateral sclerosis was generally regarded as a neuromuscular disorder, but is now recognized as a multisystemic neurological disorder. Amyotrophic lateral sclerosis generally progresses rapidly and within 2 to 5 years after diagnosis, total paralysis including dyspnea progresses and leads to death. The annual incidence of amyotrophic lateral sclerosis is 1-2 per 100,000 people, and about 10% of amyotrophic lateral sclerosis comes from family history. Except for familial amyotrophic lateral sclerosis, the cause is still unknown.
바이러스와 알루미늄 및 납 등의 중금속, 자가면역기전, 글루타메이트 같은 흥분성 신경 전달 물질, 칼슘 결합 단백 등과 관계가 있다는 등의 가설이 있으며, 이 중 근위축성측삭경화증의 발병 가설에서 중요한 기전으로 제시되고 있는 것 중의 하나가 지질대사 가설이다. There is a hypothesis that there is a relationship between viruses and heavy metals such as aluminum and lead, autoimmune mechanisms, excitatory neurotransmitters such as glutamate, and calcium binding proteins. Among these, hypothesis is suggested as an important mechanism in the onset of amyotrophic lateral sclerosis One is the lipid metabolic hypothesis.
근위축성측삭경화증은 한번 발병하면 완치하는 경우가 없는, 진행성이고 난치성의 치사성 질환임에도 불구하고, 현재 허가 받은 치료제는 흥분성 신경 전달 물질인 글루타메이트를 차단하는 약제인 릴루졸(rilozule)이 유일하나 이 또한 충분한 효과를 보이고 있지 않으며, 질병 초기단계에서 정확하게 진단하는 것이 매우 어려운 상황이다.Although amyotrophic lateral sclerosis is a progressive and intractable fatal disease that does not cure once it develops, there is only one rilozule, a drug that blocks glutamate, an excitatory neurotransmitter, In addition, it has not shown sufficient effect and it is very difficult to diagnose accurately at the early stage of disease.
WO 2008/093057는 퇴행성 신경질환의 진단을 돕는 수단에 관한 것으로서, 피검체에 존재하는 퇴행성 신경질환을 임상 평가하는 시스템 및 방법을 제공함으로써 퇴행성 신경질환의 개선된 조기 진단 및 모니터링에 도움을 주는 수단을 개시한다.WO 2008/093057 relates to a means for assisting in the diagnosis of degenerative neurological diseases and provides a system and method for clinical evaluation of degenerative neurological diseases present in a subject to provide a means for helping to improve early diagnosis and monitoring of degenerative neurological diseases .
WO 2011/111043는 근위축성측삭경화증의 조기진단에 관한 것으로서, 혈액샘플 내의 T 세포, 감마 - 델타 (γδ) T-세포, 염증성 단핵 세포, 파생 억제 세포 (MDSCs), 자연 살해 세포 중에서 선택된 적어도 하나의 셀 수준을 측정하여 비교함으로써 근위축성측삭경화증을 진단하는 방법에 대하여 개시한다.WO 2011/111043 relates to the early diagnosis of amyotrophic lateral sclerosis, wherein at least one selected from T cells in blood sample, gamma-delta (γδ) T-cells, inflammatory mononuclear cells, MDSCs, A method for diagnosing amyotrophic lateral sclerosis is described.
미국 공개특허 US2012-0322082는 근위축성측삭경화증의 진단방법 및 키트에 관한 것으로서, 인간의 단백질 HMGB1에 대한 자가항체를 포함하는 근위축성측삭경화증의 진단방법 및 이것을 포함하는 진단 키트에 대하여 개시한다.
US Patent Application Publication No. US2012-0322082 discloses a diagnostic method and kit for amyotrophic lateral sclerosis, and a diagnosis method of amyotrophic lateral sclerosis including an autoantibody to human protein HMGB1 and a diagnostic kit comprising the method.
신경 퇴행성 신경질환의 진단 또는 예후 측정에 사용될 수 있는 바이오마커를 제공하고자 한다.
And to provide a biomarker that can be used for diagnosis or prognosis of neurodegenerative neurological diseases.
한 양태에서 본원은 24-수산화 콜레스테롤 또는 25-수산화 콜레스테롤 유도체 중 하나 이상의 검출 물질을 포함하는 퇴행성 신경질환 진단 또는 예후 측정용 조성물을 제공한다. In one aspect, the present invention provides a composition for the diagnosis or prognostic evaluation of degenerative neurological diseases comprising at least one of 24-hydroxylated cholesterol or 25-hydroxylated cholesterol derivatives.
본원에 따른 일 구현예에서, 수산화 콜레스테롤 유도체 검출 물질은 액체크로마토그래피/질량분석법(LC/MS), 형광크로마토그래피, 또는 형광화학센서 중 하나 이상의 방법에 사용되는 하나 이상의 물질이나 이로 제한하는 것은 아니다. In one embodiment according to the present application, the hydroxycholesterol derivative detection material is not limited to one or more substances used in one or more of the following methods: liquid chromatography / mass spectrometry (LC / MS), fluorescence chromatography, .
본원에 따른 일 구현예에서 본원의 조성물이 사용될 수 있는 퇴행성 신경질환은 근위축성측삭경화증(ALS), 파킨슨 질환 (PD), 헌팅턴 병(Huntington's disease), 알츠하이머 질환 (AD), 일차성 측삭경화증 (PLS), 척수성 근위축증 (SMA), 니만-픽 병(Nieman-Pick disease) 또는 뇌졸중(stroke)을 포함하나 이로 제한하는 것은 아니며, 한 구현예에서는 근위축성측삭경화증(ALS)이다. In one embodiment according to the present disclosure, the degenerative neurological disorders in which the composition of the present invention can be used are selected from the group consisting of amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Huntington's disease, Alzheimer's disease (AD) PLS, spinal muscular atrophy (SMA), Nieman-Pick disease or stroke, but in one embodiment is amyotrophic lateral sclerosis (ALS).
본원은 또한 본원에 따른 조성물을 포함하는 퇴행성 신경질환 진단 또는 예후 측정용 키트를 제공한다. The present invention also provides kits for diagnosing or prognosing degenerative neurological disorders comprising a composition according to the present invention.
본원은 또한 퇴행성 신경질환의 진단에 필요한 정보를 제공하기 위해 생물학적 시료에서, 24-수산화 콜레스테롤 또는 25-수산화 콜레스테롤의 농도를 측정하는 것을 포함하는 퇴행성 신경질환 진단 또는 예후 측정용 마커 검출 방법을 제공한다. The present invention also provides a marker detection method for the diagnosis or prognostic measurement of degenerative neurological diseases comprising measuring the concentration of 24-hydroxycholesterol or 25-hydroxycholesterol in a biological sample to provide information necessary for diagnosis of degenerative neurological diseases .
본원은 또한 퇴행성 신경질환 진단 또는 예후 측정용 시스템에 있어서, (A) 퇴행성 신경질환 진단 대상자의 생물학적 시료에서 분리한 채취 물질로부터 측정되는 24-수산화 콜레스테롤 또는 25-수산화 콜레스테롤의 농도 정보를 입수하는 단계; (B) 상기 수산화 콜레스테롤 농도 정보를 처리하여, 기설정된 퇴행성 신경질환 판정 모델에 투입하는 단계 및 (C) 상기 퇴행성 신경질환 판정 모델로부터 퇴행성 신경질환 판정 정보를 생성하는 단계를 포함하는 것을 특징으로 하는 퇴행성 신경질환 진단 또는 예후 측정용 정보 제공 방법을 제공한다.
The present invention also relates to a system for diagnosing or prognosing a neurodegenerative degenerative neuropathy comprising the steps of: (A) obtaining information on the concentration of 24-hydroxycholesterol or 25-hydroxycholesterol measured from a sample collected from a biological sample of a subject diagnosed with a degenerative neurological disease ; (B) processing the above-mentioned information on the concentration of hydroxylated cholesterol to put it into a predetermined neurodegenerative disease determination model, and (C) generating degenerative neuropathy judgment information from the neurodegenerative disease determination model A method for providing information for diagnosis or prognostic measurement of degenerative neurological diseases.
본원에 따른 콜레스테롤 수산화 유도체를 검출하는 물질을 포함하는 진단용 조성물, 진단용 키트는 환자의 혈액에서 진단이 가능하므로 편리하고 신속하게 퇴행성 신경질환의 진단이 가능할 뿐만아니라 높은 재현성으로 정확성 또한 뛰어나다. Diagnostic compositions and diagnostic kits comprising a substance for detecting cholesterol hydroxylated derivatives according to the present invention can diagnose the degenerative neurological diseases conveniently and quickly since they can be diagnosed in the blood of the patient, and have high reproducibility and accuracy.
또한, 환자 시료의 콜레스테롤 수산화 유도체의 농도를 측정하여 진단함으로써 척수에서 나오는 운동신경섬유에 퇴행변성이 있어 진행성의 근위축을 야기시키는 진행성근위축증 (PMA, progreesive muscular atrophy)과 퇴행성 신경질환인 근위축석측상경화증의 구별이 가능할 뿐만 아니라, 퇴행성 신경질환의 중증도에 따라 콜레스테롤 수산화 유도체의 농도가 증가하므로 질병 중증도에 대한 정보를 제공하는 것이 용이하다. In addition, by measuring the concentration of the cholesterol hydroxyl derivative of the patient sample, it is possible to diagnose the progression of muscular atrophy (PMA), which causes progressive muscle atrophy due to degenerative degeneration of the motor nerve fibers coming from the spinal cord, It is not only possible to distinguish between sclerosis but also to increase the concentration of the cholesterol hydroxyl derivative depending on the severity of the degenerative neurological disease, so that it is easy to provide information on disease severity.
본원은 퇴행성 신경질환에서 콜레스테롤 수산화 유도체의 발현 수준을 이용하여 약물을 스크리닝하는 것이 가능하므로 콜레스테롤 수산화 유도체를 생체표지자로 치료제 후보물질의 표적으로서 이용하는 것이 가능하다.
Since the drug can be screened using the expression levels of cholesterol hydroxylated derivatives in degenerative neurological diseases, it is possible to use cholesterol hydroxylated derivatives as biomarkers as targets of therapeutic candidate substances.
도 1은 근위축성측삭경화증 환자들의 뇌척수액에서 25-수산화 콜레스테롤의 농도가 대조군과 비교하여 증가되어 있는 것을 나타내는 결과이다.
도 2는 근위축성측삭경화증 환자들의 혈청에서 25-수산화 콜레스테롤의 농도가 대조군과 비교하여 증가되어 있는 것을 나타내는 결과이다.
도 3은 근위축성측삭경화증 환자 중 치료제인 릴루졸을 복용한 환자들의 뇌척수액에서 24-수산화 콜레스테롤 및 25-수산화 콜레스테롤의 농도가 대조군과 비교하여 감소되어 있는 것을 나타내는 결과이다.FIG. 1 shows the results of an increase in the concentration of 25-hydroxylated cholesterol in cerebrospinal fluid of patients with amyotrophic lateral sclerosis compared with the control group.
FIG. 2 shows the results showing that the concentration of 25-hydroxycholesterol in the serum of the patients with amyotrophic lateral sclerosis is increased as compared with the control group.
FIG. 3 is a graph showing that the concentrations of 24-hydroxylated cholesterol and 25-hydroxylated cholesterol in cerebrospinal fluid of patients taking riluzole as a therapeutic agent in amyotrophic lateral sclerosis patients are reduced compared to the control group.
본원은 콜레스테롤 수산화 유도체와 퇴행성질환과의 관련성에 관한 발견을 근거로 한 것이다. This is based on findings of the association between cholesterol hydroxylated derivatives and degenerative diseases.
따라서 한 양태에서 본원은 본원은 콜레스테롤 수산화 유도체의 농도를 측정하기 위하여 콜레스테롤 수산화 유도체를 검출하는 물질을 포함하는 퇴행성 신경질환의 진단용 조성물을 제공한다.Accordingly, in one aspect, the present invention provides a composition for the diagnosis of a degenerative neurological disease comprising a substance that detects a cholesterol hydroxyl derivative to measure the concentration of a cholesterol hydroxylated derivative.
본원의 콜레스테롤 수산화 유도체(hydroxylated derivatives of cholesterol)는 콜레스테롤의 산화형태로 지질 대사에 있어 중요한 역할을 하는 것으로 알려져 있으며, 특히 콜레스테롤 항상성 및 동맥경화증을 포함하는 대사과정에 관련되어 있다고 알려져 있다. 콜레스테롤의 산화유도체인 콜레스테롤 수산화 유도체는 옥시스테롤(Oxysterol), 24(S), 25-에폭시콜레스테롤(24(S),25-Epoxycholesterol), 24-수산화 콜레스테롤(24-Hydroxycholesterol), 24-수산화 콜레스테롤(24-Hydroxycholesterol), 27-수산화 콜레스테롤(27-Hydroxycholesterol) 등이 있으나, 이에 한정되지는 않는다. 본 발명의 일 실시예에서는 24-수산화 콜레스테롤 또는 25-수산화 콜레스테롤을 포함한다. The hydroxylated derivatives of cholesterol are known to play an important role in lipid metabolism as an oxidized form of cholesterol and are known to be involved in metabolic processes including cholesterol homeostasis and atherosclerosis. Cholesterol hydroxyl derivatives, which are oxidative derivatives of cholesterol, include oxysterol, 24 (S), 25-epoxycholesterol (24 (S), 25-Epoxycholesterol), 24- 24-Hydroxycholesterol, 27-Hydroxycholesterol, and the like. In one embodiment of the present invention, it includes 24-hydroxycholesterol or 25-hydroxycholesterol.
본원에서 사용된 용어 “퇴행성 신경질환”은 비정상적인 신경세포의 사멸에 의하여 뇌나 척수의 기능이 마비되어 인지능력, 보행능력, 운동능력 등이 감소하게 되는 질환으로서, 근위축성측삭경화증(ALS: amyotrophic lateral sclerosis), 파킨슨병 (PD, Parkinson's disease), 헌팅턴병(HD,Huntington's disease), 알츠하이머 질환 (AD, alzheimer's disease), 일차성 측삭경화증 (PLS, Primary Lateral Sclerosis), 니만-픽 병(Nieman-Pick disease) 및 뇌졸중(stroke)과 같은 일차성 신경계의 퇴행성 질환뿐만 아니라 대사장애, 약물이나 중금속중독, 뇌염, 종양이후에 발생하는 2차성 신경질환과 소아기에 발생하는 유전질환을 포함하나, 이에 한정되는 것은 아니다. 본원에 따른 일 구현예에서는 근위축성측삭경화증의 진단에 유용하며, 특히 진행성근위축증 (PMA, progreesive muscular atrophy)과 퇴행성 신경질환인 근위축석측상경화증의 구별이 가능하다. As used herein, the term " degenerative neurological disease " refers to a disease in which the function of the brain or spinal cord is paralyzed due to abnormal neuronal death, thereby decreasing cognitive, walking, and athletic ability. Amyotrophic lateral Parkinson's disease, Huntington's disease, AD, Alzheimer's disease, Primary lateral sclerosis (PLS), Nieman-Pick disease Including, but not limited to, metabolic disorders, drug or heavy metal intoxication, encephalitis, secondary neurological disorders occurring after tumors, and genetic disorders occurring in childhood, as well as degenerative diseases of the primary nervous system, such as stroke no. In one embodiment according to the present invention, it is useful for the diagnosis of amyotrophic lateral sclerosis, and it is possible to distinguish proximal laminin sclerosis, in particular, progressive muscular atrophy (PMA) and degenerative nerve disease.
본원에서 사용된 용어 "진단"은 병리 상태의 존재 또는 특징을 확인하는 것을 의미하며, 본원의 목적을 고려하면 일 구현예에서 진단은 퇴행성 신경질환의 발병, 진행 여부 또는 진행 정도를 확인하는 것을 포함하는 개념이다.As used herein, the term "diagnosis" refers to identifying the presence or characteristic of a pathological condition, and for purposes of this disclosure, the diagnosis in one embodiment includes identifying the onset, progression, or progression of a degenerative neurological disease .
본원에서 사용된 용어 “예후”는 치료제 또는 치료에 대한 반응정도를 관찰하여, 질병의 호전여부를 판단하는 것을 의미한다. As used herein, the term " prognosis " refers to a measure of the degree of response to a therapeutic agent or treatment to determine whether the disease has improved.
본원에 사용되는 수산화 콜레스테롤 유도체 검출은 공지된 방법으로 수행될 수 있으며, 이러한 방법은 예를 들면 액체크로마토그래피/질량분석법(Liquid Chromatography-Mass spectrometry, LC/MS), 형광크로마토그래피, 또는 형광화학센서를 이용한 방법을 포함하나 이로 제한하는 것은 아니다. 이러한 방법이 기재된 문헌은 예를 들면 Kaplan et al., Clinical Chemistry: Theory, Analysis and Correlation. 3rd Ed., Mosby Company, St. Louis, Chapter 30 (1996)을 참조할 수 있다. 본원에 따른 조성물은 상기 방법에 사용되는 하나 이상의 물질을 포함할 수 있다. 예를 들면 수산화 콜레스테롤을 특이적으로 검출할 수 있는 항체가 포함될 수 있다. The detection of the hydroxylated cholesterol derivative used in the present invention can be carried out by a known method, for example, by liquid chromatography / mass spectrometry (LC / MS), fluorescence chromatography, But is not limited thereto. The literature describing such methods is described, for example, in Kaplan et al., Clinical Chemistry: Theory, Analysis and Correlation. 3rd Ed., Mosby Company, St. Louis, Chapter 30 (1996). The composition according to the invention may comprise one or more substances used in the process. For example, an antibody capable of specifically detecting hydroxylated cholesterol may be included.
다른 양태에서 본원은 또한 콜레스테롤 수산화 유도체를 검출하는 물질을 포함하는 퇴행성 신경질환의 진단용 조성물을 포함하는 퇴행성 신경질환의 진단용 키트를 제공한다.In another aspect, the present invention also provides a diagnostic kit for a degenerative neurological disease comprising a composition for the diagnosis of a degenerative neurological disease comprising a substance that detects a cholesterol hydroxylated derivative.
본원의 키트는 검사 대상 또는 검사 대상의 생물학적 시료에서 콜레스테롤 수산화 유도체의 발현을 확인하여 퇴행성 신경질환의 발병 또는 진행 정도를 진단할 수 있다. 본원에 따른 진단용 키트는 상술한 수산화 콜레스테롤 검출 방법에 사용될 수 있다. The kit of the present invention can diagnose the onset or progress of the degenerative neurological disease by confirming the expression of the cholesterol hydroxylated derivative in the biological sample to be examined or the subject to be examined. The diagnostic kit according to the present invention can be used in the above-mentioned method for detecting a hydroxylated cholesterol.
수산화 콜레스테롤 검출 방법 및 질환과 관련돼서는 앞서 서술한 바를 참조한다. See above for a discussion of methods and diseases for the detection of hydroxylated cholesterol.
본원에 따른 키트와 함께 사용되는 검체로부터 분리된 생물학적 시료는 혈액, 혈장, 혈청, 뇌척수액, 조직 또는 세포일 수 있으며, 본원의 일실시예에서는 환자로부터 분리된 혈액 또는 뇌척수액을 포함한다. The biological sample separated from the sample used with the kit according to the present application may be blood, plasma, serum, cerebrospinal fluid, tissue or cell, and in one embodiment of the present invention includes blood or cerebrospinal fluid separated from the patient.
다른 양태에서 또한 본원은 퇴행성 신경질환의 진단에 필요한 정보를 의사 또는 환자에게 제공하기 위하여 퇴행성 신경질환 진단 마커를 검출하는 방법으로서, 검체로부터 분리된 생물학적 시료에서, 콜레스테롤 수산화 유도체의 수준 또는 농도를 측정하는 것을 포함하는 퇴행성 신경질환 진단 마커를 검출하는 방법을 제공한다. In another embodiment, the invention also provides a method for detecting a marker for degenerative neurological disease diagnoses to provide a physician or a patient with the information necessary for diagnosis of a degenerative neurological disease, which comprises measuring the level or concentration of a cholesterol hydroxyl derivative in a biological sample separated from the sample And a method for detecting a neurodegenerative disease marker.
수산화 콜레스테롤 검출 방법,l 생물학적 시료 및 질환과 관련돼서는 앞서 서술한 바를 참조한다. Methods of detection of lipid cholesterol, l Refer to above for biological specimens and diseases.
나아가 본원은 또한 퇴행성 신경질환 진단용 시스템에 있어서, Further, the present invention also provides a system for diagnosing degenerative neurological diseases,
(A) 퇴행성 신경질환 진단 대상자의 생물학적 시료에서 분리한 채취 물질로부터 측정되는 콜레스테롤 수산화 유도체(24-OHC 또는 25-OHC)의 농도측정 정보를 입수하는 단계; (B) 상기 콜레스테롤 수산화 유도체 발현량 정보를 처리하여, 기설정된 퇴행성 신경질환 판정 모델에 투입하는 단계; 및 (C) 상기 퇴행성 신경질환 판정 모델로부터 퇴행성 신경질환 판정 정보를 생성하는 단계를 포함하는 것을 특징으로 하는 퇴행성 신경질환 진단용 정보 제공 방법을 제공한다.(A) obtaining information on the concentration of a cholesterol hydroxide derivative (24-OHC or 25-OHC) measured from a sample separated from a biological sample of a subject diagnosed with a degenerative neurological disease; (B) processing the information on the amount of expression of the cholesterol hydroxylated derivative and putting it into a predetermined neurodegenerative disease determination model; And (C) generating degenerative neuropathy judgment information from the degenerative neuropathy judgment model.
상기 퇴행성 신경질환 진단용 시스템은 콜레스테롤 수산화 유도체에 특이적으로 결합하는 항체를 포함하는 퇴행성 신경질환 진단 키트에서 상기 콜레스테롤 수산화 유도체의 농도 정보를 도출하는 제3의 시스템에서 실시되거나, 상기 제3의 시스템과 유무선 네트워크로 연결되며, 상기 제3의 시스템으로부터 콜레스테롤 수산화 유도체의 농도 정보를 전송받는 퇴행성 신경질환 진단 시스템에서 실시되는 것이 가능하다.The system for diagnosing degenerative neurological diseases may be carried out in a third system for deriving concentration information of the cholesterol hydroxide derivative in a degenerative neurological disease diagnostic kit comprising an antibody specifically binding to a cholesterol hydroxyl derivative, It is possible to carry out in a degenerative neurological disease diagnosis system which is connected to a wired or wireless network and receives the concentration information of cholesterol hydroxide derivative from the third system.
상기 기설정된 퇴행성 신경질환 판정 모델의 평가 지표는 정확도, 특이도, 민감도, ROC 커브의 면적 중 어느 하나 이상인 것이 바람직하다.Preferably, the evaluation index of the predetermined neurodegenerative disease model is at least one of accuracy, specificity, sensitivity, and ROC curve area.
상기 정보 입수 모듈이 상기 콜레스테롤 수산화 유도체의 농도 정보 또는 그 비율 정보를 입수하는 방법은, 상기 퇴행성 신경질환 진단 시스템이 상기 진단 키트로부터 직접 입수하는 방법, 상기 퇴행성 신경질환 진단 예측 시스템과 유무선 네트워크를 통하여 연결된 상기 진단 키트의 상기 콜레스테롤 수산화 유도체의 농도 정보를 도출할 수 있는 제3의 시스템으로부터 전송 받는 방식으로 입수하는 방법 및 상기 퇴행성 신경질환 진단 예측 시스템과 유무선 네트워크로 연결된 상기 콜레스테롤 수산화 유도체의 발현량 정보를 입수하는 자의 컴퓨터로부터 전송되는 방식으로 입수하는 방법 중 어느 하나 이상의 방법이 실시되는 것인 것이 바람직하다.The method for obtaining the information on the concentration or the ratio of the cholesterol hydroxylated derivative by the information obtaining module is a method in which the degenerative neurological disease diagnosis system obtains directly from the diagnostic kit, the degenerative neurological disease diagnosis prediction system and the wired / wireless network And a third system capable of deriving the concentration information of the cholesterol hydroxylated derivative of the diagnostic kit connected to the diagnostic kit, and a method for obtaining the cholesterol hydroxylated derivative from the diagnostic system, Or a method of obtaining data from a computer of a person who receives the data.
이하, 본원의 이해를 돕기 위해서 실시예를 제시한다. 그러나 하기의 실시예는 본원을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐 본원이 하기의 실시예에 한정되는 것은 아니다.Hereinafter, embodiments are provided to facilitate understanding of the present invention. However, the following examples are provided to facilitate understanding of the present invention, and the present invention is not limited to the following examples.
실시예 1. 근위축성측삭경화증 환자 및 대조군 모집 및 시료 채취Example 1. Recruitment and Sampling of Amyotrophic Lateral Sclerosis Patient and Control Group
근위축성측삭경화증의 진단기준인 El escorial criteria( World Federation of Neurology, 1998)을 만족시키고 근위축성측삭경화증으로 진단받은 40세 이상의 환자 중에서 발병이 3년 이내인 환자를 20명 모집하였다. 단, 경피내시경하 위루술(PEG, Percutaneous Endoscopic Gastrostomy)을 시술받았거나, 인공 호흡장치를 사용해야 하는 환자 및 L-tube feeding을 통하여 영양을 공급받아야 하는 환자는 제외하였으며, 근위축성측삭경화증의 치료제인 릴루졸(riluzole)을 투여받은 환자도 제외하였다.Twenty patients with at least 3 years of age who were diagnosed with amyotrophic lateral sclerosis who met the El escorial criteria for amyotrophic lateral sclerosis (World Federation of Neurology, 1998) and who were diagnosed with amyotrophic lateral sclerosis were recruited. Patients who underwent percutaneous endoscopic gastrostomy (PEG), who needed to use an artificial respiratory device, or those who needed nutrition through L-tube feeding were excluded, and the treatment of amyotrophic lateral sclerosis Patients receiving riluzole were also excluded.
대조군은 다른 신경계 질환을 가진 환자로 37명이 모집되었으며, 근전도(EMG, electromyogram) 검사 결과 광범위 탈신경(denervation)을 보이거나, 운동신경질환(motor neuron diseases)에 대한 임상 증거가 있는 경우, 염증성 또는 변성 중추신경계 질환을 가진 환자, 및 스테로이드 투여 경력이 있는 환자는 대조군에서 제외하였다. The control group consisted of 37 patients with other neurological diseases, and had EMG (electromyogram) as a result of extensive denervation or clinical evidence of motor neuron diseases. Patients with degenerative central nervous system disease and those with steroid administration were excluded from the control group.
환자의 동의 (informed consent)하에, 각 환자의 나이, 병력, BMI (body mass index)지수 및 혈액 내 총콜레스테롤 및 질환의 심각도(ALS functional rating scores revised, ALSFRSr)와 같은 임상 정보를 수집하였다.Clinical information such as age, history, body mass index (BMI) and total cholesterol and severity of disease (ALS functional rating scores revised, ALSFRSr) were collected under informed consent.
모집된 환자와 대조군의 혈액과 뇌척수액(cerebrospinal fluid, CSF)을 채취하여 원심분리하고 -80℃에서 보관하였다.The collected blood and cerebrospinal fluid (CSF) from the patients and controls were collected, centrifuged and stored at -80 ° C.
실시예 2. 질량분석을 이용한 하이드록시콜레스테롤 농도 측정Example 2. Measurement of the concentration of hydroxycholesterol using mass spectrometry
시료 중 24, 25, 및 27-하이드록시콜레스테롤(OHC)의 농도를 측정하기 위하여 LC/MS/MS(liquid chromatograph/Mass spectrometry/Mass spectrometry))를 사용하였다. 초고속 액체 크로마토그래피-은이온 질량분석기 (UFLC-Ag+CIS/MS/MS, Ultra fast liquid chromatography-silver ion coordination ionspray tandem mass spectrometry, Shimadzu Corporation, Kyoto, Japan)를 제조자의 방법대로 사용하였으며, 고체상 추출법(solid-phase extraction) 및 알칼리성 가수분해(alkaline hydrolysis) 기법을 공지된 방법대로 이용하여 시료를 분석하였다(Schuler, et al., Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis. J lipid research 2010 Apr;51(4):819-23)LC / MS / MS (liquid chromatograph / mass spectrometry / mass spectrometry) was used to measure the concentrations of 24, 25, and 27-hydroxycholesterol (OHC) in the samples. High speed liquid chromatography-silver ion mass spectrometry (UFLC-Ag + CIS / MS / MS, ultra fast liquid chromatography-silver ion coordination ionspray tandem mass spectrometry, Shimadzu Corporation, Kyoto, Japan) (SPL) patients with hereditary spastic paresis.J lipid research. In this study, we used a solid-phase extraction method and an alkaline hydrolysis method to analyze samples using known methods (Schuler, et al. 2010 Apr; 51 (4): 819-23)
실시예 3. 근위축성측삭경화증 환자 시료에서 콜레스테롤 수산화 유도체 농도의 증가 Example 3: Increased concentration of cholesterol hydroxylated derivatives in samples of amyotrophic lateral sclerosis patients
실시예 2의 환자의 시료 분석 결과, 도 1에서 나타난 바와 같이 대조군과 비교하여 근위축성측삭경화증을 가진 환자(n=18)의 뇌척수액에서 콜레스테롤 수산화 유도체의 농도가 0.135 ± 0.046 ng/mL로서 대조군(n=27)의 0.103 ± 0.050 ng/mL 보다 유의하게 증가되어 있음을 확인할 수 있었다. (p= 0.030)As a result of analyzing the sample of the patient of Example 2, the concentration of cholesterol hydroxylated derivative in cerebrospinal fluid of patients with amyotrophic lateral sclerosis (n = 18) was 0.135 ± 0.046 ng / mL as compared with the control group as shown in FIG. 1 n = 27), which was significantly higher than that of 0.103 ± 0.050 ng / mL. (p = 0.030)
도 2에서 나타난 바와 같이, 혈청내 콜레스테롤 수산화 유도체의 농도 역시 대조군과 비교하여 근위축성측삭경화증 환자(n=20)의 수치는 6.03 ± 3.76 ng/mL로서 대조군(n=36)의 4.22 ± 1.17 ng/mL 보다 유의하게 증가되어 있음을 확인할 수 있었다. (p= 0.027)As shown in FIG. 2, the concentration of cholesterol hydroxylated derivatives in the serum was also 6.03 ± 3.76 ng / mL in patients with amyotrophic lateral sclerosis (n = 20), which was 4.22 ± 1.17 ng in the control group (n = 36) / mL, respectively. (p = 0.027)
또한, 근위축성측삭경화증 환자 중에서 치료제인 릴루졸을 투여한 환자(n=7)의 뇌척수액 시료에서의 24-수산화 콜레스테롤의 농도 1.37 ± 0.50 ng/mL으로서 릴루졸을 투여하지 않은 환자(n=18)의 농도 2.02 ± 0.67 ng/mL에 비하여 감소되어 있었으며(p= 0.028), 25-수산화 콜레스테롤의 농도 또한 0.07 ± 0.031 ng/mL로 릴루졸 비투여 군의 농도 0.136 ± 0.046 ng/mL와 비교하여 유의하게 감소되어 있음(p= 0.001)을 확인할 수 있었다.In addition, among patients with amyotrophic lateral sclerosis, the concentration of 24-hydroxylated cholesterol in cerebrospinal fluid samples of patients treated with riluzole (n = 7) was 1.37 ± 0.50 ng / mL, ) Was lower than that of 2.02 ± 0.67 ng / mL (p = 0.028), and the concentration of 25-hydroxylated cholesterol was 0.07 ± 0.031 ng / mL compared with the concentration of 0.134 ± 0.046 ng / mL (P = 0.001), respectively.
이러한 결과는 근위축성측삭경화증 환자는 다른 기타 신경학적 증상을 가진 대조군과 비교하여 혈청과 뇌척수액 내에서 콜레스테롤 수산화 유도체가 증가되어 있다는 것을 나타내는 것으로, 환자의 치료제에 대한 반응 마커로서의 콜레스테롤 수산화 유도체가 사용될 수 있음을 나타낸다. These results indicate that patients with amyotrophic lateral sclerosis have elevated cholesterol hydroxyl derivatives in serum and cerebrospinal fluid as compared to controls with other other neurological symptoms, and cholesterol hydroxyl derivatives can be used as response markers for the patient's therapeutic agent .
이상에서 본원의 예시적인 실시예에 대하여 상세하게 설명하였지만 본원의 권리범위는 이에 한정되는 것은 아니고 다음의 청구범위에서 정의하고 있는 본원의 기본 개념을 이용한 당업자의 여러 변형 및 개량 형태 또한 본원의 권리범위에 속하는 것이다.While the present invention has been described in connection with what is presently considered to be the preferred embodiments, it is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, .
본원에서 사용되는 모든 기술용어는, 달리 정의되지 않는 이상, 본원의 관련 분야에서 통상의 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다. 본 명세서에 참고문헌으로 기재되는 모든 간행물의 내용은 본원에 도입된다. All technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs unless otherwise defined. The contents of all publications, which are incorporated herein by reference, are incorporated herein by reference.
Claims (13)
24. A composition for the diagnosis or prognosis of amyotrophic lateral sclerosis comprising at least one detection substance selected from the group consisting of 24-hydroxycholesterol and 25-hydroxycholesterol derivatives.
The method of claim 1, wherein the 24-hydroxycholesterol or 25-hydroxycholesterol derivative detection material is a substance used in one or more of the following methods: liquid chromatography mass spectrometry, fluorescence chromatography, Composition for prognostic evaluation.
The composition for diagnosing or prognosing amyotrophic lateral sclerosis according to claim 1, wherein the composition is used for judging whether or not to respond to a therapeutic agent for amyotrophic lateral sclerosis comprising riluzole.
4. The composition for diagnosing or prognosing amyotrophic lateral sclerosis according to any one of claims 1 to 3, wherein the composition is used for analysis using a blood sample.
24. A kit for the diagnosis or prognosis of amyotrophic lateral sclerosis comprising at least one detection substance of 24-hydroxycholesterol or 25-hydroxycholesterol derivative.
Diagnosis of amyotrophic lateral sclerosis including measuring the concentration of 24-hydroxycholesterol or 25-hydroxycholesterol in a biological sample to provide information necessary for diagnosis of amyotrophic lateral sclerosis or response to treatment of amyotrophic lateral sclerosis Marker Detection Method for Prognostic Measurement.
The method of claim 6, wherein the biological sample is selected from blood, plasma, serum, cerebrospinal fluid, tissue or cells.
8. The marker detection method according to claim 7, wherein the measurement of the concentration of the hydroxylated cholesterol is performed using at least one of liquid chromatography mass spectrometry, fluorescence chromatography, or fluorescence chemical sensor.
(B) 상기 수산화 콜레스테롤 농도 정보를 처리하여, 기설정된 근위축성측삭경화증 판정 모델에 투입하는 단계 및
(C) 상기 판정 모델로부터 근위축성측삭경화증 판정 정보를 생성하는 단계를 포함하는 것을 특징으로 하는 근위축성측삭경화증 진단 또는 예후 측정용 정보 제공 방법.
(A) obtaining information on the concentration of 24-hydroxycholesterol or 25-hydroxycholesterol measured from a substance isolated from a biological sample derived from a subject diagnosed with amyotrophic lateral sclerosis;
(B) processing the information on the concentration of the hydroxylated cholesterol and putting it into a predetermined amyotrophic lateral sclerosis judgment model and
(C) generating information on amyotrophic lateral sclerosis judgment from the judgment model.
12. The method of claim 11, wherein obtaining the concentration information of the cholesterol hydroxylated derivative (A) is performed using one or more of liquid chromatography mass spectrometry, fluorescence chromatography, or a fluorescence chemical sensor. A method of providing information for the diagnosis of lateral sclerosis or for prognostic measurement.
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