KR20200095669A - Prediction method of autism - Google Patents
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- KR20200095669A KR20200095669A KR1020190013264A KR20190013264A KR20200095669A KR 20200095669 A KR20200095669 A KR 20200095669A KR 1020190013264 A KR1020190013264 A KR 1020190013264A KR 20190013264 A KR20190013264 A KR 20190013264A KR 20200095669 A KR20200095669 A KR 20200095669A
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- autism
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- cytokines
- inhibitory effect
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Abstract
Description
본 발명은 자폐증의 예측방법에 관한 것으로, 보다 상세하게는 사이토카인의 발현 프로필을 측정하여 자폐증을 예측하고, 사이토카인에 대한 저해 효과를 갖는 유효 성분을 투여하여 자폐증의 발병을 억제하거나 자폐증 증상을 치료하는 방법에 관한 것이다.The present invention relates to a method for predicting autism, and more particularly, to predict autism by measuring a cytokine expression profile, and to suppress the onset of autism or to control autism symptoms by administering an active ingredient having an inhibitory effect on cytokines. It's about how to treat it.
자폐증, 자폐 스펙트럼 장애(autism spectrum disorder)는 사회적 소통에 어려움을 겪는, 다양한 종류의 연속상에 있는 일련의 장애를 통칭하는 말로, 자폐성 장애, 아스퍼거 증후군, 지적 장애, 전반적 발달 장애 등을 포함한다.Autism, autism spectrum disorder, is a collective term for a series of disorders of various types, which have difficulty in social communication, and include autistic disorder, Asperger syndrome, intellectual disability, and general developmental disability.
자폐증의 원인은 매우 복합적이나, 크게 유전적 요인(83%)과 환경적 요인 등이 관여하는 것으로 알려져 있다. 종래의 자폐증에 대한 진단은 사회적 상호작용의 질적인 면에서 명백한 점, 의사소통에서 명백한 점, 행동, 흥미, 활동의 경직된 반복과 상동행동이 현저하게 나타나는 점을 진단의 기준으로 하여 판단할 수 있다.The causes of autism are very complex, but it is known that genetic factors (83%) and environmental factors are largely involved. The conventional diagnosis of autism can be judged based on the obvious points in the quality of social interaction, the obvious points in communication, the rigid repetition of behaviors, interests, activities, and remarkable homologous behaviors. .
최근에는 유전적 요인의 규명을 위한 유전체 시퀀싱 기법을 이용하여, 자폐증 환자의 유전체 분석 및 빅데이터 활용을 통하여 자폐증의 원인과 관련된 유전자들이 발견되고 있으나, 이에 대한 상세한 생물학적 검증이 요구되므로, 효율성이 낮다. 연구에 따르면, 자폐 아동과 비자폐 아동의 혈액 내 단백질에 유의미한 차이가 있으며, 혈액과 소변에 포함되어 있는 혈장 단백질 및 아미노산을 안정동위원소 분석법을 사용해 조사함으로써, 혈장 단백질이 다이타이로신(dityrosine)의 생체 지표를 남기며, 자폐증을 앓으면 단백질에 최종당화산물(AGEs)이라는 유해물질이 쌓이는 것으로부터, 자폐아와 비자폐아의 혈중 다이타이로신 농도 비교를 통해 자폐증 예측이 가능하게 되었다. 그러나, 상기 방법의 예측 정확도는 60~70% 수준으로, 보다 높은 예측 정확도를 갖는 방법의 개발이 필요한 상황이다.Recently, genes related to the cause of autism have been discovered through genome analysis of autistic patients and the use of big data using genome sequencing techniques for identification of genetic factors, but since detailed biological verification is required, the efficiency is low. . According to the study, there is a significant difference in the protein in the blood of children with autism and non-autism, and plasma proteins and amino acids in blood and urine were investigated using stable isotope analysis, so that plasma proteins were found to be dityrosine. Autism can be predicted by comparing the blood levels of dityrosine between autistic and non-autistic children, as it leaves biomarkers, and because harmful substances called AGEs accumulate in proteins when autism occurs. However, the prediction accuracy of the method is at the level of 60 to 70%, and development of a method with higher prediction accuracy is required.
본 발명은 사이토카인의 시간에 따른 발현 프로필을 측정하여 자폐증을 예측하고, 사이토카인에 대한 저해 효과를 갖는 유효 성분을 투여하여 자폐증의 발병을 억제하거나 자폐증 증상을 치료하는 것을 목적으로 한다.An object of the present invention is to predict autism by measuring the expression profile of cytokines over time, and to suppress the onset of autism or to treat autism symptoms by administering an active ingredient having an inhibitory effect on cytokines.
본 발명의 자폐증의 예측방법은 대상체의 생후 직후~1.5년 사이에 2회 이상 피부 및 혈액 샘플을 수집하는 단계;; 및 상기 샘플로부터 사이토카인(cytokine)의 시간에 따른 발현 프로필을 측정하는 단계;를 포함한다.The method for predicting autism of the present invention comprises the steps of collecting skin and blood samples at least twice between immediately after birth to 1.5 years of the subject; And measuring a time-dependent expression profile of cytokines from the sample.
본 발명의 일 예에 따른 자폐증의 예측방법에 있어서, 상기 사이토카인은 Th1, Th2 및 Th17로 이루어진 군에서 선택되는 어느 하나 또는 둘 이상을 포함할 수 있다.In the method for predicting autism according to an embodiment of the present invention, the cytokine may include any one or two or more selected from the group consisting of Th1, Th2, and Th17.
본 발명의 일 예에 따른 자폐증의 예측방법에 있어서, 상기 사이토카인의 시간에 따른 발현 양상이 생후 직후~7개월에서 Th1 또는 Th17 사이토카인이 정상아에 비해 1.5배 이상, 5개월 이후~1년에서 Th2 사이토카인이 정상아에 비해 1.5배 이상 각각 증가하는 경우 자폐증으로 판정하는 단계;를 더 포함할 수 있다.In the method for predicting autism according to an embodiment of the present invention, the expression pattern of the cytokine according to time is from immediately after birth to 7 months after birth, and the Th1 or Th17 cytokine is 1.5 times higher than that of normal infants, and from 5 months to 1 year. The step of determining as autism when the Th2 cytokine increases by 1.5 times or more, respectively, compared to the normal infant; may further include.
본 발명의 일 예에 따른 자폐증의 예측방법에 있어서, 상기 피부 및 혈액 샘플의 수집 간격은 2개월 이상일 수 있다.In the method for predicting autism according to an embodiment of the present invention, the collection interval of the skin and blood samples may be 2 months or more.
본 발명의 자폐증 치료를 위한 투여 방법은 생후 직후~1.5년 사이의 대상체에 Th1 또는 Th17 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함하는 조성물을 투여한 후, 순차적으로 Th2 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함하는 조성물을 투여하는 단계를 포함한다.The administration method for the treatment of autism of the present invention is after administering a composition containing an active ingredient having an inhibitory effect on Th1 or Th17 cytokine to a subject between immediately after birth to 1.5 years, and then sequentially inhibiting effect on Th2 cytokine. It includes the step of administering a composition containing the active ingredient having.
본 발명의 일 예에 따른 자폐증 치료를 위한 투여방법에 있어서, 상기 생후 직후~1.5년 사이의 대상체에 항 인터페론 감마 사이토카인 항체(anti-IFN-γ cytokine antibody)를 유효성분으로 포함하는 조성물을 투여하고, 순차적으로 항 Th2 사이토카인 항체(anti-Th2 cytokine antibody)를 유효성분으로 포함하는 조성물을 투여하는 단계를 포함할 수 있다.In the administration method for the treatment of autism according to an embodiment of the present invention, a composition comprising an anti-IFN-γ cytokine antibody as an active ingredient is administered to a subject between immediately after birth and 1.5 years of age. And, it may include the step of sequentially administering a composition comprising an anti-Th2 cytokine antibody (anti-Th2 cytokine antibody) as an active ingredient.
본 발명의 일 예에 따른 자폐증 치료를 위한 투여방법에 있어서, 상기 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함하는 조성물을 투여하는 간격은 2개월 이상일 수 있다.In the administration method for the treatment of autism according to an embodiment of the present invention, the interval between administering a composition containing an active ingredient having an inhibitory effect on cytokines may be 2 months or more.
본 발명의 일 예에 따른 자폐증 치료를 위한 투여방법에 있어서, 상기 투여방법은 피부 도포, 피하 주사, 경구 투여를 포함하는 것인 상기 유효성분을 피부에 도포하거나 피하 주사할 수 있다.In the method of administration for the treatment of autism according to an embodiment of the present invention, the method of administration includes skin application, subcutaneous injection, and oral administration. The active ingredient may be applied to the skin or injected subcutaneously.
본 발명의 자폐증 발병 억제 또는 자폐증 증상 치료용 약학적 조성물은 Th1 또는 Th17 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함하는 조성물 및 Th2 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함한다.The pharmaceutical composition for inhibiting the onset of autism or treating autism symptoms of the present invention includes a composition comprising an active ingredient having an inhibitory effect on Th1 or Th17 cytokines, and an active ingredient having an inhibitory effect on Th2 cytokines.
본 발명의 자폐증 발병 억제 또는 자폐증 증상 개선용 화장료 조성물은 Th1 또는 Th17 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함하는 조성물 및 Th2 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함한다.The cosmetic composition for suppressing the onset of autism or improving symptoms of autism of the present invention comprises a composition comprising an active ingredient having an inhibitory effect on Th1 or Th17 cytokines, and an active ingredient having an inhibitory effect on Th2 cytokines.
본 발명의 자폐증 발병 억제 또는 자폐증 증상 개선용 건강기능식품은 Th1 또는 Th17 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함하는 조성물 및 Th2 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함한다.The health functional food for suppressing the onset of autism or improving symptoms of autism of the present invention includes a composition comprising an active ingredient having an inhibitory effect on Th1 or Th17 cytokines, and an active ingredient having an inhibitory effect on Th2 cytokines.
본 발명에 따른 자폐증의 예측방법은 사이토카인의 발현 프로필을 측정하여 자폐증을 예측하는 것으로, 태어난 직후 대상에 대하여, 단기간의 사이토카인 발현 프로필의 측정만으로 자폐증을 조기에 예측할 수 있으며, 본 발명에 따른 자폐증의 치료를 위한 방법은 태어난 직후의 대상에 대해 사이토카인 발현 억제 물질을 유효성분으로 포함하는 조성물을 투여함으로써 단기간 내에 자폐증의 발현 억제, 자폐증의 개선 및 치료에 대한 효과가 뛰어나다.The method for predicting autism according to the present invention is to predict autism by measuring a cytokine expression profile, and for a subject immediately after birth, autism can be predicted early only by measuring a short-term cytokine expression profile, according to the present invention. The method for the treatment of autism is excellent in suppressing the expression of autism within a short period of time, improving autism, and treating it by administering a composition containing a cytokine expression inhibitor as an active ingredient to a subject immediately after birth.
도 1은 TNFα에 대한 피부 및 뇌에서의 시간에 따른 발현 프로필이다.
도 2는 IFNγ에 대한 피부 및 뇌에서의 시간에 따른 발현 프로필이다.
도 3은 IL-17A에 대한 피부 및 뇌에서의 시간에 따른 발현 프로필이다.
도 4는 IL-4에 대한 피부 및 뇌에서의 시간에 따른 발현 프로필이다.
도 5는 IL-13에 대한 피부 및 뇌에서의 시간에 따른 발현 프로필이다.
도 6은 IL-5에 대한 피부 및 뇌에서의 시간에 따른 발현 프로필이다.1 is an expression profile of TNFα over time in skin and brain.
2 is an expression profile of IFNγ over time in skin and brain.
3 is an expression profile of IL-17A over time in skin and brain.
4 is an expression profile for IL-4 in skin and brain over time.
5 is an expression profile of IL-13 over time in skin and brain.
6 is an expression profile of IL-5 over time in skin and brain.
이하 첨부한 표 또는 도면들을 참조하여 본 발명의 자폐증의 예측방법에 대해 상세히 설명한다.Hereinafter, a method for predicting autism according to the present invention will be described in detail with reference to the accompanying tables or drawings.
도면이 기재되어 있을 경우, 이는 당업자에게 본 발명의 사상이 충분히 전달될 수 있도록 하기 위해 예로서 제공되는 것이다. 따라서 본 발명은 제시되는 도면들에 한정되지 않고 다른 형태로 구체화될 수도 있으며, 상기 도면들은 본 발명의 사상을 명확히 하기 위해 과장되어 도시될 수 있다.When the drawings are described, this is provided as an example in order to sufficiently convey the spirit of the present invention to those skilled in the art. Accordingly, the present invention is not limited to the drawings to be presented and may be embodied in other forms, and the drawings may be exaggerated to clarify the spirit of the present invention.
이때, 사용되는 기술 용어 및 과학 용어에 있어서 다른 정의가 없다면, 이 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 통상적으로 이해하고 있는 의미를 가지며, 하기의 설명 및 첨부 도면에서 본 발명의 요지를 불필요하게 흐릴 수 있는 공지 기능 및 구성에 대한 설명은 생략한다.At this time, unless there are other definitions in the technical terms and scientific terms used, they have the meanings commonly understood by those of ordinary skill in the art to which this invention belongs, and the gist of the present invention in the following description and accompanying drawings Descriptions of known functions and configurations that may be unnecessarily blurred will be omitted.
또한 본 발명의 명세서에서 사용되는 단수 형태는 문맥에서 특별한 지시가 없는 한 복수 형태도 포함하는 것으로 의도할 수 있다. In addition, the singular form used in the specification of the present invention may be intended to include the plural form unless otherwise indicated in the context.
또한 본 발명의 명세서에서 특별한 언급 없이 사용된 단위는 중량을 기준으로 하며, 일 예로 % 또는 비의 단위는 중량% 또는 중량비를 의미한다.In addition, units used in the specification of the present invention are based on weight, and as an example, the unit of% or ratio means weight% or weight ratio.
또한 본 발명의 명세서에서, “포함한다”는 표현은 “구비한다”, “함유한다”, “가진다” 또는 “특징으로 한다” 등의 표현과 등가의 의미를 가지는 개방형 기재이며, 추가로 열거되어 있지 않은 요소, 재료 또는 공정을 배제하지 않는다. 또한 “실질적으로…로 구성된다”는 표현은 특정된 요소, 재료 또는 공정과 함께 열거되어 있지 않은 다른 요소, 재료 또는 공정이 발명의 적어도 하나의 기본적이고 신규한 기술적 사상에 허용할 수 없을 만큼의 현저한 영향을 미치지 않는 양으로 존재할 수 있는 것을 의미한다. 또한 “구성된다”는 표현은 기재된 요소, 재료 또는 공정만이 존재하는 것을 의미한다.In addition, in the specification of the present invention, the expression "includes" is an open type description having a meaning equivalent to expressions such as "have", "include", "have" or "feature", and are additionally listed. It does not exclude elements, materials or processes that do not exist. Also, “substantially… The expression “consists of” means that the specified element, material or process does not have an unacceptably significant influence on at least one basic and novel technical idea of the invention by other elements, materials or processes not listed. It means something that can exist as a quantity. Also, the expression “consisting of” means that only the described elements, materials or processes are present.
본 발명의 명세서에서 사용된 용어, "성분", "조성물", "화합물의 조성물", "화합물", "약물", "약학적 활성제", "활성제", "치유" "치료법" "치료" 또는 "약제"는 대상체(인간 또는 동물)에 투여될 때 국소 및/또는 전신 작용에 의해 원하는 약학적 및/또는 생리학적 효과를 유도하는 화합물 또는 화합물(들) 또는 물질의 조성물을 의미하기 위해 상호교환적으로 사용된다.Terms used in the specification of the present invention, "ingredient", "composition", "composition of a compound", "compound", "drug", "pharmaceutical active", "active agent", "healing" "treatment" "treatment" Or “pharmaceutical” means a compound or a composition of compound(s) or substances that induces a desired pharmaceutical and/or physiological effect by local and/or systemic action when administered to a subject (human or animal). It is used interchangeably.
본 발명의 명세서에서 사용된 용어 "치료" 또는 "치료법"(뿐만 아니라 그의 상이한 형태)는 예방적 (예: 예방적 치료), 치유적 또는 경감성 치료를 포함한다. 본원에서 사용된 용어 "치료하는"은 상태, 질환 또는 장애의 적어도 하나의 유해 또는 부정적 효과 또는 증상을 경감시키거나 감소시키는 것을 포함한다. The term “treatment” or “treatment” (as well as different forms thereof) as used herein includes prophylactic (eg, prophylactic treatment), curative or palliative treatment. The term "treating" as used herein includes alleviating or reducing at least one adverse or negative effect or symptom of a condition, disease or disorder.
본 발명에 있어 “샘플” 또는 “시료”는 분석을 위한 대상을 나타내는 것으로, 명세서에 걸쳐 동일한 의미로 사용되었다.In the present invention, "sample" or "sample" refers to an object for analysis, and has the same meaning throughout the specification.
이하 본 발명에 대해 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 자폐증의 예측방법은 대상체의 생후직후~1.5년 사이에 2회 이상 피부 및 혈액 샘플을 수집하는 단계;; 및 상기 샘플로부터 사이토카인(cytokine)의 시간에 따른 발현 프로필을 측정하는 단계;를 포함하며, 바람직하게 상기 샘플의 수집은 대상체의 생후직후~6개월 및 6개월 이후~1년 사이에 각각 2회 이상 수집하는 것이 신속 정확한 자폐증의 예측을 위해 좋으나, 이에 한정하는 것은 아니다.The method for predicting autism of the present invention comprises the steps of collecting skin and blood samples at least twice between immediately after birth to 1.5 years of the subject; And measuring the expression profile of cytokines over time from the sample; and, preferably, collection of the sample is performed twice between immediately after birth of the subject to 6 months and between 6 months and 1 year. Collecting the above is good for rapid and accurate prediction of autism, but is not limited thereto.
일반적으로, 사람에 있어서의 자폐증 진단은 출생 후, 2년 이상이 경과하여 사람들을 응시하는 등의 사회적 활동 여부, 타인과의 의사 소통, 사람과의 접촉 여부에 있어 일반적인 사람과 다른 형태의 반응을 보이는 것으로부터 판단이 가능하나, 이 경우, 시간이 경과할수록 자폐증 치료가 성공적으로 이루어지는 확률이 현저히 떨어지는 문제점이 있다. 따라서, 상기와 같은 자폐 증상을 보이기 이전에, 자폐 가능성이 있는지를 미리 예측하여 자폐 증상의 발현 억제, 자폐 증상의 치료를 수행하는 것이 매우 중요하며, 본 발명에서는 생후직후로부터 짧은 기간 내에 자폐증 여부를 예측하고, 이에 대한 치료를 수행하는 점에서 그 효과가 현저하다.In general, the diagnosis of autism in humans is a response different from that of ordinary people in terms of social activities such as staring at people, communication with others, and contact with people more than two years after birth. Although it is possible to judge from what is visible, in this case, there is a problem that the probability of successful treatment of autism decreases over time. Therefore, it is very important to prevent the expression of autism symptoms and treat autism symptoms by predicting the possibility of autism in advance before showing the autism symptoms as described above, and in the present invention, whether or not there is autism within a short period of time after birth The effect is remarkable in that it predicts and performs treatment for it.
상기 대상체로부터 샘플을 수집할 때, 대상체의 수집 간격의 기준은 사람의 평균 수명을 기준으로 할 수 있으며, 이로부터 다른 종류의 생물체의 평균 수명을 환산함으로써, 샘플 수집 간격을 환산할 수 있다. 일예로, 본 발명의 일 실시예에 따른 쥐 또는 랫트는 인간에 비해 수명이 0.025 내지 0.05배, 상세하게는 0.03 내지 0.05배, 더욱 상세하게는 0.04 내지 0.05배 정도이나, 본 발명의 범위가 이에 한정하는 것은 아니다. 본 발명에 사용한 쥐 나이를 사람의 나이로 환산은 Sulagna Dutta 등이 2016년도에 Life Science에 보고한 논문(Men and Mice: Relating their ages)을 기준으로 하였다. 보고에 따르면 40일 사람 나이는 1일 쥐 나이에 상응하기 때문에, 쥐 1일은 사람 40일(약 1개월), 쥐 4일은 사람 160일(약 5~6개월), 쥐 12일은 사람 480일(약 1년 6개월), 쥐 21일은 사람 840일(약 2.5년~3년)에 상응한다. When collecting samples from the subject, the standard of the collection interval of the subject may be based on the average lifespan of a person, and by converting the average lifespan of other types of organisms from this, the sample collection interval may be converted. For example, a rat or rat according to an embodiment of the present invention has a lifespan of 0.025 to 0.05 times, specifically 0.03 to 0.05 times, and more specifically 0.04 to 0.05 times compared to humans, but the scope of the present invention is thus It is not limiting. The age of the mice used in the present invention was converted to the age of humans based on a paper (Men and Mice: Relating their ages) reported to Life Science in 2016 by Sulagna Dutta et al. According to reports, since the 40-day human age corresponds to the 1-day rat age, 1 rat day is human 40 days (about 1 month),
사이토카인은 신체의 방어체계를 제어하고 자극하는 신호물질 단백질로서, 면역, 염증 및 조혈계에 속한 세포와 관련하여 세포 상호작용의 유도와 조절에 주된 역할을 하고, 인체의 면역체계를 제어하고 자극하는 중심 역할을 수행하기 때문에 세포성 및 체액성면역 반응, 염증 반응의 유도, 항암 작용, 항바이러스 작용, 조혈의 조절, 세포의 증식˙분화의 조절 등에 중요한 기능을 한다. 이는 환경성 화학 물질 노출에 의해 발현이 변화하는 중요한 인자로서 면역 독성 측면에서 또한 중요한 의미를 가진다.Cytokines are signaling substances proteins that control and stimulate the body's defense system, play a major role in inducing and regulating cell interactions in relation to cells belonging to the immune, inflammatory and hematopoietic systems, and control and stimulate the body's immune system. Because it plays a central role, it plays an important role in cellular and humoral immune response, induction of inflammatory response, anticancer action, antiviral action, regulation of hematopoiesis, and regulation of cell proliferation and differentiation. This is an important factor whose expression is changed by exposure to environmental chemicals, and has important implications in terms of immunotoxicity.
상기 발현 프로필의 측정은 효소결합면역법(Enzyme-linked immunosorbent assay; ELISA), 면역 블롯(immunoblotting), 조직면역 염색, 면역침강, FACS, 단백질 칩 및 면역형광으로 구성된 군으로부터 선택되는 어느 하나의 방법으로 측정할 수 있으나, 이에 한정되는 것은 아니며, 상황에 맞는 적절한 측정 방법을 선택하여 측정할 수 있다.The expression profile measurement is by any one method selected from the group consisting of enzyme-linked immunosorbent assay (ELISA), immunoblotting, tissue immunostaining, immunoprecipitation, FACS, protein chip and immunofluorescence. Although it can be measured, it is not limited thereto, and it can be measured by selecting an appropriate measurement method suitable for the situation.
본 발명의 일 예에 따른 자폐증의 예측방법에 있어서, 상기 사이토카인은 Th1, Th2 및 Th17로 이루어진 군에서 선택되는 어느 하나 또는 둘 이상을 포함할 수 있다.In the method for predicting autism according to an embodiment of the present invention, the cytokine may include any one or two or more selected from the group consisting of Th1, Th2, and Th17.
상기 Th1은 TNF-α 및 인터페론 감마(IFN-γ)에서 선택되는 어느 하나 또는 둘 이상을 포함할 수 있고, 상기 Th2는 IL-4, IL-5 및 IL-13으로 이루어진 군에서 선택되는 어느 하나 또는 둘 이상을 포함할 수 있으며, 상기 Th17은 IL-17A를 포함할 수 있으나 이에 한정하는 것은 아니다.The Th1 may include any one or two or more selected from TNF-α and interferon gamma (IFN-γ), and the Th2 is any one selected from the group consisting of IL-4, IL-5 and IL-13 Alternatively, two or more may be included, and Th17 may include IL-17A, but is not limited thereto.
본 발명의 일 예에 따른 자폐증의 예측방법에 있어서, 상기 사이토카인의 시간에 따른 발현 프로필이 생후직후~7개월에서 Th1 또는 Th17 사이토카인이 1.5배 이상, 5개월 이후~1년에서 Th2 사이토카인이 1.5배 이상 각각 증가하는 경우 자폐증으로 판정하는 단계;를 더 포함할 수 있으며, 바람직하게 상기 발현 프로필이 생후직후~6개월에서 Th1 또는 Th17 사이토카인이 2배 이상, 6개월 이후~1년에서 Th2 사이토카인이 2배 이상 각각 증가하는 경우, 보다 정확하게 자폐증으로 판정할 수 있어 좋으나, 이에 한정하는 것은 아니다.In the method for predicting autism according to an embodiment of the present invention, the expression profile of the cytokine over time is 1.5 times more than the Th1 or Th17 cytokine from immediately after birth to 7 months, and the Th2 cytokine from 5 months to 1 year. The step of determining as autism when each of these increases by 1.5 times or more; may further include, and preferably, the expression profile is at least 2 times the Th1 or Th17 cytokine from immediately after birth to 6 months, from 6 months to 1 year. If the Th2 cytokine is increased by two or more, it is good that it can be more accurately determined as autism, but is not limited thereto.
본 발명의 일 실시예에 의하면, 본 발명의 자폐증 예측 대상 모델인 쥐에 대하여, 태어난 직후부터, 21일 경과시까지 사이토카인의 시간에 따른 프로필을 측정하였으며, 측정 결과에 의하면, 태어난 직후 Th1 및 Th17 사이토카인의 발현이 증가함을 확인하였으며, 이러한 프로필이 4일째까지 증가하는 결과를 확인하였으며, 이후에는 Th2의 발현이 증가하는 반면, Th1 및 Th17 사이토카인의 발현량은 전반적으로 감소하는 결과를 얻었다.According to an embodiment of the present invention, with respect to the rat, which is a target model for predicting autism of the present invention, a profile of cytokines over time was measured from immediately after birth to 21 days, and according to the measurement results, Th1 and It was confirmed that the expression of Th17 cytokine was increased, and this profile was confirmed to increase up to the 4th day. After that, the expression of Th2 was increased, whereas the expression level of Th1 and Th17 cytokine was generally decreased. Got it.
상기 결과를 사람에 대해 적용하면, 약 6개월 시점까지 Th1 및 Th17이 높은 프로필을 보여주고, 이후 Th2의 발현이 증가하는 반면, Th1 및 Th17 사이토카인의 발현량은 전반적으로 감소하는 것을 확인하였다.When the above results were applied to humans, it was confirmed that Th1 and Th17 showed a high profile up to the time point of about 6 months, and then the expression of Th2 increased, while the expression level of Th1 and Th17 cytokines decreased overall.
본 발명에 따른 상기 결과는 자폐증 예측방법에 있어 전혀 알려진 바가 없는 새로운 것으로, 상기와 같은 경향을 이용하여, 상기 사이토카인 발현 프로필을 시간에 따라 측정할 수 있는 방법을 적용함으로써, 태어난 직후의 대상체에 대한 자폐증 여부를 빠른 시기에 판단할 수 있는 장점이 있다.The results according to the present invention are new, which are not known at all in the autism prediction method, and by applying a method capable of measuring the cytokine expression profile over time using the same trend, the subject immediately after birth It has the advantage of being able to quickly determine whether or not you have autism.
본 발명의 일 예에 따른 자폐증의 예측방법에 있어서, 상기 피부 및 혈액 샘플의 수집 간격은 2개월 이상, 좋게는 3개월 이상 5개월 이하일 수 있으며, 상기 간격으로 샘플을 수집하여 자폐증 여부를 판단할 때, 사이토카인의 발현량의 변화를 보다 명확하게 판단할 수 있고, 자페증 증상이 심화되기 전에 자폐증 여부를 미리 예측하는 것이 가능하다.In the method for predicting autism according to an embodiment of the present invention, the collection interval of the skin and blood samples may be 2 months or more, preferably 3 months or more and 5 months or less, and the samples are collected at the intervals to determine whether autism is present. At this time, it is possible to more clearly determine the change in the expression level of cytokines, and it is possible to predict in advance whether autism or not before the autism symptoms worsen.
이하 본 발명의 자폐증 치료를 위한 투여방법에 대해 상세히 설명한다.Hereinafter, an administration method for the treatment of autism of the present invention will be described in detail.
본 발명의 자폐증 치료를 위한 투여방법은 생후직후~1.5년 사이의 대상체에 Th1 또는 Th17 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함하는 조성물을 투여한 후, 순차적으로 Th2 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함하는 조성물을 투여하는 단계를 포함한다.The administration method for the treatment of autism of the present invention is after administering a composition containing an active ingredient having an inhibitory effect on Th1 or Th17 cytokine to a subject between immediately after birth to 1.5 years, and then sequentially inhibiting effect on Th2 cytokine. It includes the step of administering a composition containing the active ingredient having.
본 발명의 자폐증 치료를 위한 투여방법은 생후직후~6개월의 대상체에 Th1 또는 Th17 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함하는 조성물을 투여하고, 6개월 이후의 대상에 Th2 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함하는 조성물을 투여하는 단계를 포함한다.The administration method for the treatment of autism of the present invention is to administer a composition containing an active ingredient having an inhibitory effect on Th1 or Th17 cytokine to a subject immediately after birth to 6 months, and to a subject after 6 months against Th2 cytokine. It includes administering a composition containing an active ingredient having an inhibitory effect.
본 발명의 일 예에 따른 자폐증 치료를 위한 투여방법에 있어서, 상기 생후직후~1.5년 사이의 대상체에 항 인터페론 감마 사이토카인 항체(anti-IFN-γ cytokine antibody)를 유효성분으로 포함하는 조성물을 투여하고, 순차적으로 항 Th2 사이토카인 항체(anti-Th2 cytokine antibody)를 유효성분으로 포함하는 조성물을 투여하는 단계를 포함할 수 있다.In the administration method for the treatment of autism according to an embodiment of the present invention, a composition comprising an anti-IFN-γ cytokine antibody as an active ingredient is administered to a subject between immediately after birth and 1.5 years. And, it may include the step of sequentially administering a composition comprising an anti-Th2 cytokine antibody (anti-Th2 cytokine antibody) as an active ingredient.
본 발명의 일 예에 따른 자폐증 치료를 위한 투여방법에 있어서, 상기 생후직후~6개월의 대상에 항 인터페론 감마(anti-IFN-γ)를 유효성분으로 포함하는 조성물을 투여하고, 상기 6개월 이후의 대상에 항 Th2 사이토카인 항체(anti-Th2 cytokine antibody)를 유효성분으로 포함하는 조성물을 투여하는 단계를 포함할 수 있다.In the administration method for the treatment of autism according to an embodiment of the present invention, a composition containing anti-interferon gamma (anti-IFN-γ) as an active ingredient is administered to the subject immediately after birth to 6 months, and after 6 months It may include the step of administering a composition containing an anti-Th2 cytokine antibody as an active ingredient to the target of.
본 발명의 일 예에 따른 자폐증 치료를 위한 투여방법에 있어서, 상기 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함하는 조성물을 투여하는 간격은 2개월 이상, 좋게는 3개월 이상 5개월 이하일 수 있으며, 상기 간격으로 샘플을 수집하여 자폐증 여부를 판단할 때, 사이토카인의 발현량의 변화를 보다 명확하게 판단할 수 있고, 자페증 증상이 심화되기 전에 자폐증 여부를 미리 예측하는 것이 가능하다.In the administration method for the treatment of autism according to an embodiment of the present invention, the interval between administering a composition containing an active ingredient having an inhibitory effect on cytokines may be 2 months or more, preferably 3 months or more and 5 months or less, and , When determining whether autism or not by collecting samples at the above intervals, it is possible to more clearly determine the change in the expression level of cytokines, and it is possible to predict whether autism in advance before autism symptoms worsen.
본 발명의 일 예에 따른 자폐증 치료를 위한 투여방법에 있어서, 상기 투여방법은 피부 도포, 피하 주사, 경구 투여를 포함하는 것인 상기 유효성분을 피부에 도포하거나 피하 주사할 수 있다.In the method of administration for the treatment of autism according to an embodiment of the present invention, the method of administration includes skin application, subcutaneous injection, and oral administration. The active ingredient may be applied to the skin or injected subcutaneously.
본 발명의 자폐증 발병 억제 또는 자폐증 증상 치료용 약학적 조성물은 Th1 또는 Th17 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함하는 조성물 및 Th2 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함한다.The pharmaceutical composition for inhibiting the onset of autism or treating autism symptoms of the present invention includes a composition comprising an active ingredient having an inhibitory effect on Th1 or Th17 cytokines, and an active ingredient having an inhibitory effect on Th2 cytokines.
상기 약학적 조성물은 유효성분에 통상의 무독성 약제학적으로 허용 가능한 담체 및 부형제 등을 첨가하여 약제학적 분야에서 통상적인 제제, 예를 들면 정제, 환제, 경연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭서제(elixirs) 등의 경구투여용 제제 또는 정맥내, 피하, 설하, 근육내 투약용 멸균성 수성 또는 오일상 용제의 비경구투여용 제제로 제제화할 수 있다. The pharmaceutical composition is a conventional formulation in the pharmaceutical field, such as tablets, pills, soft capsules, liquids, suspensions, emulsifiers, syrups, by adding a conventional non-toxic pharmaceutically acceptable carrier and excipient to the active ingredient. , Granules, elixirs, etc., or a sterile aqueous or oily formulation for parenteral administration for intravenous, subcutaneous, sublingual, intramuscular administration.
본 발명의 약학적 조성물에 사용될 수 있는 약제학적으로 허용 가능한 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및/또는 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention are commonly used in formulation, and are lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin. , Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and/or mineral oil, etc. , But is not limited thereto.
본 발명의 약학적 조성물에 사용될 수 있는 부형제로는 감미제, 결합제, 용해제, 용해보조제, 습윤제, 유화제, 등장화제, 흡착제, 붕해제, 산화방지제, 방부제, 활탁제, 충진제, 방향제 등이 있으며, 이러한 부형제의 비율 및 성질은 선택된 정제의 용해도 및 화학적 특성, 선택된 투여경로 및 표준 약제 실무에 의해 결정될 수 있다. 부형제의 예로는 락토스, 덱스트로스, 슈크로스, 만니톨, 솔비톨, 셀룰로오스, 글라이신, 실리카, 탈크, 스테아린산, 스테린, 마그네슘 스테아린산염, 마그네슘 알루미늄 규산염, 녹말, 젤라틴, 트라가칸트 고무, 알지닌산, 소디움 알진산염, 메틸셀룰로오스, 소디움 카르복실메틸셀룰로오스, 아가, 물, 에탄올, 폴리에틸렌글리콜, 폴리비닐피롤리돈, 염화나트륨, 염화칼슘, 오렌지 엣센스, 딸기 엣센스, 바닐라 향 등을 들 수 있다. Excipients that can be used in the pharmaceutical composition of the present invention include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, tonicity agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, and the like. The proportions and properties of excipients can be determined by the solubility and chemical properties of the selected tablet, the route of administration chosen, and standard pharmaceutical practice. Examples of excipients include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearic acid, magnesium stearate, magnesium aluminum silicate, starch, gelatin, rubber tragacanth, arginic acid, Sodium alginate, methylcellulose, sodium carboxylmethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, and the like.
또한, 본 발명의 약학적 조성물은 비경구 투여 형태로 제형화될 수도 있는데, 이러한 경우 정맥 내 투여, 복강 내 투여, 근육 내 투여, 피하 투여 또는 국부 투여 등을 이용할 수 있으나, 이에 제한되지 않는다. 이 때, 상기 비경구 투여용 제형으로 제제화하기 위하여, 상기 약학적 조성물은 유효성분이 안정제 또는 완충제와 함께 물에서 혼합되어 용액 또는 현탁액으로 제조되고, 이러한 용액 또는 현탁액이 앰플 또는 바이알의 단위 투여형으로 제조될 수 있다.In addition, the pharmaceutical composition of the present invention may be formulated in a parenteral dosage form. In this case, intravenous administration, intraperitoneal administration, intramuscular administration, subcutaneous administration, or topical administration may be used, but are not limited thereto. At this time, in order to formulate the formulation for parenteral administration, the pharmaceutical composition is prepared as a solution or suspension by mixing the active ingredient in water with a stabilizer or buffer, and such a solution or suspension is a unit dosage form of an ampoule or vial. Can be manufactured.
또한, 본 발명의 약학적 조성물은 멸균되거나, 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제를 더 포함할 수도 있고, 기타 치료적으로 유용한 물질을 더 포함할 수도 있으며, 혼합, 과립화 또는 코팅의 통상적인 방법에 따라 제제화될 수 있다.In addition, the pharmaceutical composition of the present invention may be sterilized or further contain adjuvants such as preservatives, stabilizers, hydrating agents or emulsifying accelerators, salts for controlling osmotic pressure, and/or buffers, and other therapeutically useful substances. Alternatively, it may be formulated according to conventional methods of mixing, granulating or coating.
또한, 본 발명에 따른 약학적 조성물에서 유효성분의 사람을 포함하는 포유류에 대한 투여용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질병정도에 따라 달라질 수 있다. 일반적으로 하루에 0.001 내지 500 ㎎/㎏(체중), 바람직하게는 0.01 내지 100 ㎎/㎏(체중)의 유효량으로 상기 약제학적 조성물에 포함될 수 있고, 이러한 약학적 조성물은 1 일 1 회 또는 2 회 이상 분할되어 경구 또는 비경구적 경로를 통해 투여될 수 있다. 그러나, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.In addition, the dosage of the active ingredient in the pharmaceutical composition according to the present invention to mammals including humans may vary depending on the patient's age, weight, sex, dosage form, health condition, and disease severity. In general, it may be included in the pharmaceutical composition in an effective amount of 0.001 to 500 mg/kg (body weight) per day, preferably 0.01 to 100 mg/kg (body weight), and such pharmaceutical compositions may be used once or twice a day. It can be divided and administered through an oral or parenteral route. However, since it may increase or decrease depending on the route of administration, the severity of the disease, sex, weight, age, etc., the dosage amount is not limited by any method.
본 발명의 자폐증 발병 억제 또는 자폐증 증상 개선용 화장료 조성물은 Th1 또는 Th17 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함하는 조성물 및 Th2 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함한다.The cosmetic composition for suppressing the onset of autism or improving symptoms of autism of the present invention comprises a composition comprising an active ingredient having an inhibitory effect on Th1 or Th17 cytokines, and an active ingredient having an inhibitory effect on Th2 cytokines.
또한, 본 발명은 상기 유효성분을 포함하는 화장료 조성물을 제공한다.In addition, the present invention provides a cosmetic composition comprising the active ingredient.
본 발명에서 상기 화장료 조성물은 제한되지는 않으나 용액, 현탁액, 유탁액, 페이스트, 겔, 크림, 로션, 파우더, 비누, 오일, 분말 파운데이션, 유탁액 파운데이션, 왁스 파운데이션 및 스프레이로 구성된 군으로부터 선택되는 어느 하나의 제형일 수 있다.In the present invention, the cosmetic composition is not limited, but any selected from the group consisting of solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, oil, powder foundation, emulsion foundation, wax foundation, and spray. It can be a single formulation.
상기 화장료 조성물은 유효성분 이외에 화장품에 통상적으로 이용되는 성분들을 포함할 수 있으며, 예컨대 항산화제, 안정화제, 용해화제, 비타민, 안료 및 향료와 같은 통상적인 보조제, 그리고 담체를 포함할 수 있다.In addition to the active ingredient, the cosmetic composition may include ingredients commonly used in cosmetics, and may include conventional adjuvants such as antioxidants, stabilizers, solubilizers, vitamins, pigments and fragrances, and a carrier.
한편, 상기 화장료 조성물은 당업계에서 통상적으로 제조되는 어떠한 제형으로도 제조될 수 있으며, 예를 들어, 용액, 현탁액, 유탁액, 페이스트, 겔, 크림, 로션, 파우더, 비누, 계면활성제-함유 클린싱, 오일, 분말 파운데이션, 유탁액 파운데이션, 왁스 파운데이션 및 스프레이 등으로 제형화될 수 있다. 다만, 이에 반드시 한정되는 것은 아니다. 더욱 상세하게는, 유연 화장수, 수렴 화장수, 영양 화장수, 영양 크림, 마사지 크림, 에센스, 팩, 스프레이 또는 파우더의 제형으로 제조될 수 있다.On the other hand, the cosmetic composition may be prepared in any formulation conventionally prepared in the art, for example, solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing , Oil, powder foundation, emulsion foundation, wax foundation and spray can be formulated. However, it is not necessarily limited thereto. More specifically, it may be prepared in the form of a flexible lotion, astringent lotion, a nutrition lotion, a nutrition cream, a massage cream, an essence, a pack, a spray, or a powder.
상기 화장료 조성물의 제형이 페이스트, 크림 또는 겔인 경우에는 담체 성분으로서 동물성유, 식물성유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크 또는 산화아연 등이 이용될 수 있다.When the formulation of the cosmetic composition is a paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide are used as carrier components. Can be.
또한, 본 발명의 화장품의 제형이 파우더 또는 스프레이인 경우에는 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄 히드록시드, 칼슘 실리케이트 또는 폴리아미드 파우더가 이용될 수 있고, 특히 스프레이인 경우에는 추가적으로 클로로플루오로히드로카본,프로판/부탄 또는 디메틸 에테르와 같은 추진체를 포함할 수 있다.In addition, when the formulation of the cosmetic product of the present invention is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. In particular, in the case of a spray, additional chlorofluoro Propellants such as hydrocarbon, propane/butane or dimethyl ether.
또한, 본 발명의 화장품의 제형이 용액 또는 유탁액인 경우에는 담체 성분으로서 용매, 용해화제 또는 유탁화제가 이용되고, 예컨대 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸글리콜오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜 또는 소르비탄의 지방산 에스테르가 사용될 수 있다.In addition, when the cosmetic formulation of the present invention is a solution or emulsion, a solvent, a solubilizing agent or an emulsifying agent is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, Propylene glycol, 1,3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or fatty acid ester of sorbitan can be used.
또한, 본 발명의 화장품의 제형이 현탁액인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상의 희석제, 에톡실화이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 및 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가 또는 트라칸트 등이 사용될 수 있다.In addition, when the formulation of the cosmetic product of the present invention is a suspension, as a carrier component, a liquid diluent such as water, ethanol or propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, and polyoxyethylene sorbitan ester are suspended. Agent, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tracant, and the like may be used.
본 발명의 자폐증 발병 억제 또는 자폐증 증상 개선용 건강기능식품은 Th1 또는 Th17 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함하는 조성물 및 Th2 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함한다.The health functional food for suppressing the onset of autism or improving symptoms of autism of the present invention includes a composition comprising an active ingredient having an inhibitory effect on Th1 or Th17 cytokines, and an active ingredient having an inhibitory effect on Th2 cytokines.
본 발명에서 '건강기능식품'이란 영양소를 한 가지 또는 그 이상 함유하고 있는 천연물 또는 가공품을 의미하며, 바람직하게는 식품에 물리적, 생화학적, 생물공학적 수법 등을 이용하여 해당 식품의 기능을 특정 목적에 작용, 발현하도록 부가가치를 부여한 식품군이나 식품 조성이 갖는 생체방어리듬조절, 질병방지와 회복 등에 관한 체조절기능을 생체에 대하여 충분히 발현하도록 설계하여 가공한 식품을 의미한다. 건강기능식품에는 식품학적으로 허용 가능한 식품 보조 첨가제를 포함할 수 있으며, 건강기능식품의 제조에 통상적으로 사용되는 적절한 담체, 부형제 및 희석제를 더욱 포함할 수 있다.In the present invention, the term'health functional food' refers to a natural product or processed product containing one or more nutrients, and preferably uses physical, biochemical, and biotechnological techniques in the food for specific purposes. It refers to foods that have been designed and processed to sufficiently express the function of exercise for the regulation of biological defense rhythms, disease prevention and recovery, etc. of a food group or food composition that has added value to act and express to the living body. The health functional food may contain food additives that are acceptable food additives, and may further include suitable carriers, excipients, and diluents commonly used in the manufacture of health functional foods.
본 발명의 유효성분을 첨가할 수 있는 건강기능식품으로는 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제 등이 있다. 추가로, 특수영양식품(예, 조제유류, 영,유아식 등), 건강보조식품, 과자류(예, 스넥류), 유가공품(예, 발효유, 치즈 등), 기타 가공식품, 음료(예, 과실,채소류 음료, 두유류, 발효음료류 등) 등을 포함하나 이에 한정되지 않는다. 상술된 식품, 음료 또는 식품첨가제는 통상의 제조방법으로 제조될 수 있다.Health functional foods to which the active ingredient of the present invention can be added include, for example, various foods, beverages, gum, tea, and vitamin complexes. In addition, special nutritional foods (e.g., formula, infants, baby food, etc.), health supplements, confectionery (e.g., snacks), dairy products (e.g., fermented milk, cheese, etc.), other processed foods, beverages (e.g. fruits, vegetables, etc.) Beverages, soy milk, fermented beverages, etc.), but are not limited thereto. The above-described food, beverage or food additive may be prepared by a conventional manufacturing method.
본 발명의 건강기능식품은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 물, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 이러한 성분을 독립적으로 또는 조합하여 사용할 수 있다.The health functional foods of the present invention include various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickeners (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and its It may contain salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, water, carbonation agents used in carbonated beverages, and the like. These components may be used independently or in combination.
이와 같이 본 발명의 건강기능식품은 상술된 바와 같이 다양한 제형을 갖을 수 있으며, 특히 분말, 과립, 정제, 캡슐 및 음료 등에서 어느 하나의 제형을 가질 수 있으나, 이에 한정되는 것은 아니다.As described above, the health functional food of the present invention may have various formulations as described above, and in particular, may have any one formulation in powders, granules, tablets, capsules and beverages, but is not limited thereto.
이하, 본 발명의 내용을 실시예를 통하여 보다 구체적으로 설명한다. 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것일 뿐, 본 발명의 권리범위가 이들에 의해 한정되는 것은 아니다.Hereinafter, the content of the present invention will be described in more detail through examples. The examples are only for describing the present invention in more detail, and the scope of the present invention is not limited thereto.
[실험재료, 시약 및 장비] [Test materials, reagents and equipment]
- 암컷 임신 BALB/c마우스: 대한바이오링크, 한국-Female pregnant BALB/c mouse: Daehan Biolink, Korea
- 발프로산(valproic acid): 시그마알드리치, 미국-Valproic acid: Sigma-Aldrich, USA
- 사이토카인 측정 키트: 써모-피셔, 미국-Cytokine measurement kit: Thermo-Fischer, USA
- 기타 시약은 Sigma, Merck에서 구입하여 사용하였다.-Other reagents were purchased from Sigma and Merck and used.
- 기타 측정기기는 대한민국에서 구입하여 사용하였다.-Other measuring devices were purchased and used in Korea.
[[ 실시예Example 1] One] 사이토카인 발현 프로필 측정Cytokine expression profile measurement
적정 동물 모델로 BALB/c 임신중인 암컷 마우스 2마리를 선정하고, 대조군 암컷에 대해서는 12.5일째에 1 x PBS를 주사하고, 실험군 암컷에 대해서는 12.5일째에 발프로산(valproic acid)을 600 mg/kg으로 주사하였다.Two BALB/c pregnant female mice were selected as an appropriate animal model, and 1×PBS was injected on the 12.5 day for the control female, and 600 mg/kg valproic acid on the 12.5 day for the experimental female. Was injected.
상기 암컷으로부터 출생한 생후 1일째의 마우스를 희생하여 피부 조직 샘플을 가로x세로 각각 1 cm로 잘라내고, 뇌 조직을 적출하여 중량을 측정한 후, 적당한 양으로 잘라 튜브에 수득하였다. 수득한 조직 샘플은 액체 질소를 이용하여 순간 동결시킨 후 -80℃에 보관하였다.A mouse born from the female on the first day of birth was sacrificed, and a skin tissue sample was cut into 1 cm each in width x length, and the brain tissue was removed to measure the weight, and then cut into an appropriate amount to obtain a tube. The obtained tissue sample was instantly frozen using liquid nitrogen and then stored at -80°C.
조직 전체 단백질의 분리Isolation of whole tissue proteins
상기 실시예 1의 샘플로부터 각각 전체 단백질을 분리하였다.Total protein was isolated from each of the samples of Example 1.
상기 뇌 조직으로부터의 전체 단백질 추출은 단백질 분해효소 저해제(protease inhibitor) 및 포스파타아제 억제제(phosphatase inhibitor)가 포함된 용출 버퍼(lysis buffer; 65 mM Tris buffer (pH7.4), 155 mM sodium chloride, 1 mM EDTA, 0. 25% (w/v) sodium deoxycholate (Sigma), 1% (v/v) IGEPAL (Sigma, USA))를 사용하여 분리하였다. Extraction of the total protein from the brain tissue is an elution buffer (lysis buffer; 65 mM Tris buffer (pH 7.4), 155 mM sodium chloride) containing a protease inhibitor and a phosphatase inhibitor. Isolation was performed using 1 mM EDTA, 0.25% (w/v) sodium deoxycholate (Sigma), 1% (v/v) IGEPAL (Sigma, USA)).
-80℃에서 보관된 상기 뇌 조직에 상기 용출 버퍼를 1 ㎖씩 첨가하여 균질화(homogenization)한 후, 14,000 rpm, 4℃ 조건에서 10분간 원심 분리하였다. 원심 분리 후, 단백질 샘플인 상층액만을 취해서 새로운 튜브에 넣어 -80℃에서 보관한다. 각 전체 단백질 시료의 농도는 BCA 방법을 이용하여 측정하였다.After homogenization by adding 1 ml of the elution buffer to the brain tissue stored at -80°C, it was centrifuged for 10 minutes at 14,000 rpm and 4°C. After centrifugation, only the supernatant, which is a protein sample, is taken and put into a new tube and stored at -80°C. The concentration of each total protein sample was measured using the BCA method.
면역 반응 및 발현량의 측정Measurement of immune response and expression level
상기 과정을 통해 수득한 전체 단백질 샘플 5 ㎍를 블로킹(blocking)된 96well 플레이트에 첨가하여 4℃에서 하룻 밤 반응시켰다. 세척 과정을 거친 후, 사이토카인의 종류만큼 샘플을 분리하여 실험군을 준비하고, 각 사이토카인에 대한 검출 항체(detection antibody cocktail) 0.1 ㎖씩 첨가하여 4℃에서 하룻 밤 반응시켰다. 세척 과정을 거친 후, HRP-streptavidin(스트렙아비딘) 0.1 ㎖를 첨가하여 실온에서 2시간 동안 반응시켰다.5 µg of a total protein sample obtained through the above process was added to a blocked 96 well plate and reacted overnight at 4°C. After the washing process, samples were separated according to the types of cytokines to prepare an experimental group, and 0.1 ml of a detection antibody cocktail for each cytokine was added and reacted at 4° C. overnight. After the washing process, 0.1 ml of HRP-streptavidin (streptavidin) was added and reacted at room temperature for 2 hours.
반응이 완료된 후 검출 버퍼(detection buffer)를 사용하여 표준품의 정량곡선에 대입하여 샘플마다 정량치를 나타내었다.After the reaction was completed, a detection buffer was used to substitute it into a quantification curve of a standard product, and a quantification value was shown for each sample.
4일, 12일, 21일 경과시 면역 반응Immune response after 4, 12, and 21 days
상기와 같은 방법으로, 생후 4일째, 12일째 및 21일째의 마우스를 각각 희생하여 피부 조직 샘플을 가로x세로 각각 1 cm로 잘라내고, 뇌 조직을 적출하여 중량을 측정한 후, 적당한 양으로 잘라 튜브에 수득하였다. 수득한 조직 샘플은 액체 질소를 이용하여 순간 동결시킨 후 -80℃에 보관하였다.In the same manner as described above, mice at the 4th, 12th, and 21st days of life were sacrificed, and a skin tissue sample was cut into 1 cm each in width x length, and brain tissue was removed to measure the weight, and then cut into an appropriate amount. Obtained in a tube. The obtained tissue sample was instantly frozen using liquid nitrogen and then stored at -80°C.
상기와 동일한 방법으로 조직의 단백질을 분리하고, 면역반응을 통해 각 사이토카인의 량을 정량 측정하였다.Tissue proteins were isolated in the same manner as described above, and the amount of each cytokine was quantitatively measured through an immune response.
하기 표 1에 상기 과정을 통해 측정한 사이토카인의 정량치를 보기 쉽게 도식화하여 나타내었다. In Table 1 below, the quantitative values of cytokines measured through the above process are schematically shown for easy viewing.
(정상 마우스 대비 자폐 유도 마우스의 사이토카인 수치로 변환, ↑↑: 많이 증가, ↑: 증가, -: 변동없음, ↓: 감소)(Converted to cytokine levels in autism-inducing mice compared to normal mice, ↑↑: increased, ↑: increased, -: no change, ↓: decreased)
[[ 실시예Example 2] 마우스 자폐증 모델에 대한 자폐증 치료를 위한 투여 2] Administration for the treatment of autism in mouse autism model
상기 실시예 1에서 발프로산(valproic acid)을 주사하여 유도한 자폐증 모델 마우스에 대하여, 생후 1일~4일까지 항 인터페론 감마 사이토카인 항체(anti-IFN-γ cytokine antibody)를 하루 1회씩 투여한 후, 4일 경과 후부터 12일 경과시까지 항 IL-5 사이토카인 항체(anti-IL-5 cytokine antibody)를 하루 2회씩 주사 투여하였다.To the autism model mouse induced by injection of valproic acid in Example 1, an anti-interferon gamma cytokine antibody was administered once a day from 1 to 4 days of age. Then, from 4 days to 12 days, an anti-IL-5 cytokine antibody was injected twice a day.
이후 30일 경과할 때까지 마우스의 활동을 관찰한 결과, 반복적인 행동의 횟수가 현저히 감소하여, 상기 사이토카인 저해제의 투여를 통해 증상이 개선된 것을 확인할 수 있었다.As a result of observing the activity of the mouse until the lapse of 30 days thereafter, the number of repetitive actions significantly decreased, and it was confirmed that symptoms were improved through administration of the cytokine inhibitor.
[[ 실시예Example 3] 고등 동물에 대한 자폐증 치료를 위한 투여 3] Administration for the treatment of autism in higher animals
자폐증을 가진 부부 사이에서 출생한 자폐 의심 신생아 3명에 대해 생후 직후부터 6개월이 경과할 때까지 항 인터페론 감마 사이토카인 항체(anti-IFN-γ cytokine antibody)를 하루 1회씩 투여한 후, 6개월 이후부터 1년 경과시까지 항 IL-5 사이토카인 항체(anti-IL-5 cytokine antibody)를 하루 2회씩 주사 투여하였다.Anti-interferon gamma cytokine antibody (anti-IFN-γ cytokine antibody) once a day was administered once a day for 3 newborns suspected of autism born between a couple with autism from immediately after birth to 6 months, followed by 6 months From then to the elapse of 1 year, anti-IL-5 cytokine antibody was injected twice a day.
이후 3세가 될 때까지 신생아의 행동을 관찰하여, 자폐 증상이 나타나는지 확인하였다.After that, the newborn's behavior was observed until the age of 3, and it was confirmed that autism symptoms appeared.
그 결과, 3명 모두에서 대표적인 자폐증 증상인 의사소통에 별다른 문제점이 발생하지 않았고, 반복적인 행동을 거의 나타내지 않아, 자폐증의 주요 증상을 나타내지 않았으며, 이로부터, 본 발명의 사이토카인 억제제를 유효성분으로 포함하는 조성물의 투여를 통해 자폐 증상의 발현을 억제하고, 자폐증을 개선 또는 치료하는 효과가 있음을 발견하여 본 발명을 완성하였다.As a result, in all three patients, no other problem occurred in communication, which is a typical symptom of autism, and there was little repetitive behavior, so that the main symptoms of autism were not exhibited, and from this, the cytokine inhibitor of the present invention was used as an active ingredient. The present invention was completed by finding that there is an effect of suppressing the expression of autism symptoms and improving or treating autism through administration of a composition comprising as.
[[ 제형예Formulation example 1] One]
하기 표 2 및 표 3의 조성으로 통상의 방법에 따라 연고를 제조하였다.An ointment was prepared according to a conventional method with the composition of Table 2 and Table 3 below.
Claims (11)
상기 샘플로부터 사이토카인(cytokine)의 시간에 따른 발현 프로필을 측정하는 단계;
를 포함하는 자폐증의 예측방법.Collecting skin and blood samples at least twice between immediately after birth of the subject to 1.5 years; And
Measuring the expression profile of cytokines over time from the sample;
Autism prediction method comprising a.
상기 사이토카인은 Th1, Th2 및 Th17로 이루어진 군에서 선택되는 어느 하나 또는 둘 이상을 포함하는 자폐증의 예측방법According to claim 1,
The cytokine is a method for predicting autism comprising any one or two or more selected from the group consisting of Th1, Th2 and Th17
상기 사이토카인의 시간에 따른 발현 프로필이 생후 직후~7개월에서 Th1 또는 Th17 사이토카인이 1.5배 이상, 5개월 이후~1년에서 Th2 사이토카인이 1.5배 이상 각각 증가하는 경우 자폐증으로 판정하는 단계;
를 더 포함하는 자폐증의 예측방법.According to claim 1,
The step of determining autism when the expression profile of the cytokine according to time increases by 1.5 times or more in Th1 or Th17 cytokines in the immediate to 7 months after birth, and 1.5 times or more in the Th2 cytokines in 1 year after 5 months;
Autism prediction method further comprising.
상기 피부 및 혈액 샘플의 수집 간격은 2개월 이상인 자폐증의 예측방법.According to claim 1,
A method for predicting autism in which the collection interval of the skin and blood samples is 2 months or more.
상기 생후직후~1.5년 사이의 대상체에 항 인터페론 감마 사이토카인 항체(anti-IFN-γ cytokine antibody)를 유효성분으로 포함하는 조성물을 투여하고, 순차적으로 항 Th2 사이토카인 항체(anti-Th2 cytokine antibody)를 유효성분으로 포함하는 조성물을 투여하는 단계를 포함하는 자폐증 치료를 위한 투여방법.The method of claim 5,
A composition containing an anti-IFN-γ cytokine antibody as an active ingredient is administered to the subject between immediately after birth and 1.5 years, followed by an anti-Th2 cytokine antibody. A method of administration for the treatment of autism comprising administering a composition comprising as an active ingredient.
상기 사이토카인에 대한 저해 효과를 갖는 유효성분을 포함하는 조성물을 투여하는 간격은 2개월 이상인, 자폐증 치료를 위한 투여방법.The method of claim 5,
The interval between administering the composition containing the active ingredient having an inhibitory effect on the cytokine is 2 months or more, an administration method for the treatment of autism.
상기 투여방법은 피부 도포, 피하 주사, 경구 투여를 포함하는 것인 상기 유효성분을 피부에 도포하거나 피하 주사하는 것인, 자폐증 치료를 위한 투여방법.The method according to any one of claims 5 to 7,
The administration method is to apply the active ingredient to the skin or subcutaneously injection, including skin application, subcutaneous injection, oral administration, administration method for the treatment of autism.
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| KR (1) | KR20200095669A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20180015126A (en) | 2015-04-14 | 2018-02-12 | 스티븐 호프만 | Compositions and methods for treating autism |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20180015126A (en) | 2015-04-14 | 2018-02-12 | 스티븐 호프만 | Compositions and methods for treating autism |
Non-Patent Citations (2)
| Title |
|---|
| Chisato Tawada et al. J. Invest. Dematol. 134:712-718 (2014). |
| Kenneth R. Feingold, J. Invest. Dematol. 134:597-600 (2014). |
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