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Prediction and prophylactic treatment of type 1 diabetesPrediction and prophylactic treatment of type 1 diabetes description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20080026378, Prediction and prophylactic treatment of type 1 diabetes. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001]This invention relates to methods for the prediction of type 1 diabetes, and in particular, to a method for predicting the probable onset of type I diabetes in children by measuring circulating levels of metabolites in blood, and also to methods for the prophylactic treatment of type 1 diabetes. [0002]Diabetes mellitus ("diabetes") is a medical disorder characterised by persistent variable hyperglycemia (i.e. high blood sugar levels). It can result from either inadequate secretion of the hormone insulin, an inadequate response by the body to insulin, or a combination of these factors. The most common forms of diabetes are type 1, type 2 and gestational diabetes. [0003]Type 1 diabetes (T1D, also known as "childhood", "juvenile" or "insulin-dependent" diabetes) is most commonly diagnosed in children and adolescents. It is an autoimmune disorder, in which the patient's own immune system attacks the beta cells in the Islets of Langerhans of the pancreas--where insulin is produced, and/or the insulin molecule itself. Consequently, patients with clinical T1D require regular insulin replacement therapy, immunosuppression treatment or even more experimental therapies such as islet transplantation and stem cell therapy. However, none of these treatments are ideal. While insulin replacement therapy and immunosuppression require longterm treatment and cannot irradicate all diabetes induced complications, islet transplantation and stem cell therapy are not widely available and are very expensive. [0004]Throughout the world the percentage incidence of T1D is increasing, and this is especially true of the early onset form of T1D, which affects children under the age of 4 yrs. Currently in North America T1D affects approximately 1 in 300 people and accounts for approximately 10% of all diabetic cases. T1D is a multigenetic disorder, with up to 20 genes known to contribute. Of these, the major genetic susceptibility determinants are the human leukocyte antigen (HLA) class II alleles, HLA-DR and HLA-DQ, which are associated with up to 50% of all T1D cases. However, genetic factors alone cannot account for a person's susceptability to the disease. For instance, less than 10% of new T1D patients have an affected family member, while the concordance between genetically identical twins is only approximately 50%. In addition, the incidence of T1D is rising far too rapidly to be attributed merely to the inheritance of diabetogenic genes. Thus, it is widely acknowledged that non-genetic, environmental factors (e.g. nutrition, infectious agents) must also play an important role in either the triggering or progression of the disease process, or both. [0005]Indeed, several prospective studies have suggested that factors operating early in life may play an important role in the etiopathogenesis of T1D (Akerblom H. K. et al., 2002, Am. J. Med. Genet. May, 115(1), 18-29). Amongst the environmental factors that may be involved, dietary factors operating early in life, i.e. short breast feeding, early exposure to cow's milk, early introduction of gluten, have been suggested to increase the risk of developing the disease (Virtanen S. M. & Knip M. 2003, Am. J. Clin. Nutr., December, 78(6), 1053-1067; and Ziegler A. G. et al., 2003, J. Am. Med. Assoc., October, 290(13), 1721-1728). [0006]The non-genetic factors that contribute to T1D susceptibility are even less well defined than the genetic factors. In particular, there is little verifiable evidence of the specific contribution of non-genetic factors to T1D or how such factors interact with and influence the known genetic predeterminants. [0007]The clinical onset (i.e. the insulin-dependent stage) of T1D is preceded by a sub-clinical phase, that can last up to several years, during which the insulin-producing islet cells and/or the patient's insulin are progressively destroyed. The sub-clinical phase is typically characterised by the presence of autoantibodies, which target one or more of the subject's islet cells (islet cell antibodies, ICAs), insulin (insulin autoantibodies, IAAs), glutamic acid decarboxylase (glutamic acid decarboxylase autoantibodies, GADAs) and tyrosine phosphatase (tyrosine phosphatase autoantibodies, IA-2As). Accordingly, there is potentially a window of opportunity during which subjects at risk of T1D may be identified for preventative therapy. [0008]Increasingly, combinations of markers are being used to better define the risk of diabetes. However, while the detection of two or more types of autoantibody (ICA, IAA, GADA and IA-2A) has been linked to the future onset of diabetes, significant problems remain in the selection and identification of subjects having a high probability of developing T1D, and especially of children vulnerable to the early-onset form. [0009]In this regard, until now, the selection of candidates for T1D predictive testing has largely focussed on those subjects who have a family member already with the disease. However, with a less than 10% familial correlation, this approach is entirely inadequate to provide an effective means of identifying 90% of eventual T1D patients for intervention therapy. Hence, there is a need for a reliable, effective and simple method for predicting susceptibility or predisposition to T1D, that can be readily used for large-scale screening of the general population, rather than of specific genetic sub-groups. [0010]Although children who develop early-onset T1D (i.e. in the period 0-4 yrs) may show signs of IAAs even from birth, it is not possible to distinguish neonatal autoantibodies from transplacental maternal IgGs in the first year of life. Accordingly, of those neonatal children tested and found positive for particular autoantigens, the vast majority may not ultimately develop T1D. [0011]In view of the rising incidence of T1D in children, the lack of a suitable method for predicting the likely onset of T1D in children, and in view of the potential for an early intervention therapy if it is predicted sufficiently early in children, it would be particularly desirable to have an effective method of predicting T1D in children, especially in the first few days of life. [0012]Moreover, given the current lack of a definitive cure for T1D, the need for frequent, tightly controlled medication, and the potentially fatal consequences of a lapse in the treatment regime, the most important driver for detecting individuals who are at risk of developing T1D is the potential for a preventative therapy. Thus, it would be desirable to provide a prophylatic treatment regime for preventing or at least delaying the onset of T1D. [0013]This invention aims to overcome or alleviate the problems associated with the prior art. [0014]In light of the above, in prospective studies into the development of early-onset T1D, the inventors have surprisingly found that neonatal children who go on to develop T1D before the age of 4 yrs, display reduced levels of circulating amino acids in the first few days of life (e.g. 0-3 days), compared with children who do not develop T1D. Significantly, this trend is apparent irrespective of whether the subject has a low, moderate or high genetic predisposition to T1D based on his or her HLA genotype. [0015]Thus, in accordance with a first aspect of the invention, there is provided an in vitro method for predicting the onset of type 1 diabetes (T1D) in a subject, comprising the steps of: [0016](a) measuring the concentration of at least one amino acid, amino acid derivative or amino acid metabolite in a biological sample taken from the subject; [0017](b) determining the subject's HLA genotype; [0018](c) assigning the subject's genetic risk of developing T1D on the basis of the subject's HLA genotype; [0019](d) combining the information obtained in step (a) with the information in step (c); and [0020](e) predicting the likelihood of onset of T1D based upon the combination of step (d). [0021]The amount of one or more amino acid can be measured in a number of relatively simple, quick and cost-effective ways, making the method of the invention a simple, reliable, quick and economical way of predicting the likelihood of future onset of T1D in a subject. [0022]Thus, compared with prior art processes for predicting the development of T1D, the method of the invention has the advantage that it can be performed universally (i.e. on any subject, not just those whom have already been identified as being within a genetically high-risk group). [0023]Indeed, the inventors have surprisingly found that the method of the invention can be used to predict the likelihood of onset of T1D in any member of the population, for example, subjects whom, according to their genetic markers, may be classified as "high", "moderate"/"medium" or "low" risk. Preferably, the genetic risk is classified according to the subject's HLA genotype. [0024]The risk of developing T1D associated with particular HLA genotypes has been reported by a number of research groups (Redondo M. J. et al., 2001, Recent Prog. Horm. Res. 56: 69-89; Ilonen J. et al., 2002, Am. J. Med. Genet. 115(1): 30-6; Mimbacas, A. et al., 2003, Gen. Mole. Res., 2(1), 29-35; Lambert, A. P. et al., 2004, J. Clin. Endocrinol. Metab., 89(8), 4037-4043; and Buzzetti R. et al., 2004, Diabetes Metab. Res. Rev., 20(2), 137-143). The skilled person in the art will appreciate that since the method of the invention is applicable to subjects having high, medium or low risk HLA genotypes, the method of assigning such high, medium or low genetic risk categories is not essential to the performance of the invention. Preferably, however, the subject is assigned a genetic risk according to categorisation reported in Buzzetti R. et al. (2004, Diabetes Metab. Res. Rev., March-April, 20(2), 137-143), the teaching of which is incorporated herein in its entirety. [0025]Hence, a high risk HLA genotype typically comprises the genetic markers: [0026]DRB1*03/*04 (not 0403), DQB1 0302. [0027]A moderate or medium risk HLA genotype typically comprises the genetic markers: [0028]DRB1*04 (not 0403)/*04 (not 0403), DQB1 0302; [0029]DRB1*04 (not 0403)/X, DQB1 0302/DQB1 not 0602-3) [0030]DRB1*03/*03; and [0031]DRB1*03/X, DQB1 not 0602-3, not 0301, not 0503;wherein X is not DRB1*03, *04, or 0403. [0032]A low risk HLA genotype comprises any combination of genetic markers not specified above. [0033]In step (a) of the first aspect of the invention, the concentration of one or more amino acid, and/or amino acid derivative and/or amino acid metabolite is measured in a sample taken from a subject. [0034]The term "amino acid" within the scope of the present invention is used in its broadest sense and is meant to include naturally occurring L .alpha.-amino acids or residues. The commonly used one and three letter abbreviations for naturally occurring amino acids are used herein (Lehninger, A. L., 1975, Biochemistry, 2d ed., pp. 71-92, Worth Publishers, New York). The general term "amino acid" further includes D-amino acids, where such occur naturally in the human or animal body. The term amino acid also encompasses naturally occurring amino acids that are not usually incorporated into proteins such as norleucine. Continue reading about Prediction and prophylactic treatment of type 1 diabetes... Full patent description for Prediction and prophylactic treatment of type 1 diabetes Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Prediction and prophylactic treatment of type 1 diabetes patent application. 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