Methods and kits for determining a personalized treatment regimen for a subject suffering from a pathologic disorder

Abstract

The invention relates to methods and kits for determining and optimizing a personalized treatment regimen for a subject suffering from a pathologic disorder based on calculating the value of M, that indicates the ability of said subject to eliminate said disorder. The invention specifically relates to optimization of interferon treatment of viral disorders.

1 . A method for determining a personalized treatment regimen for a subject suffering from a pathologic disorder, said method comprises the step of:
 a. Calculating the value of M, wherein said value indicates the ability of said subject to eliminate said disorder;   b. Determining the value of M1, said value indicates the minimal ability required for eliminating said disorder;   c. providing the dose A1 and number B1 of administrations of said dose to obtain an amount C1 of said medicament required for eliminating said disorder in subjects having a value of M that is equal or above said M1 value, wherein A1*B1=C1;   d. Calculating the dose A and number B of administrations of said dose A to obtain an amount C1 required for said subject having said M determined/calculated in step (a), wherein said A=A1/(M1/M) and B=B1*(M1/M); thereby at least one of determining and optimizing the treatment regimen for said subject.   
     
     
         2 . The method according to  claim 1 , wherein calculating the value of M is performed by the steps of any one of:
 I. A static analysis comprising:
 Ia. determining the level of expression of at least one of ISG15, IFIT1, IFIT2, IFITM3, IFIT3, IFIT5, OAS1, OAS2, OAS3, OASL, HERC5, USP18, RSAD2, MX, IFI44L, DDX58, UBE1L, UBE2L6, IFI27, IFIH1, TLR7, IRF7, IFI6, STAT1, IFI44, EIF2AK2 and DHX58 genes in a biological sample of said subject, to obtain an expression value Ex samp  in said sample; 
 Ib. providing a standard curve of expression values of subjects suffering from the same pathologic disorder; 
 Ic. Obtaining a maximal expression value Ex max  and a minimal expression value Ex min  from said standard curve of (Ib); and 
 Id. Calculating the M value of said sample, wherein M=1−[(Ex samp −Ex min )/(Ex max −Ex min ]; 
   II. An induced dynamic analysis comprising:
 IIa. determining the level of expression of at least one of genes in a biological sample of said subject, to obtain an expression value in said sample; 
 IIb. exposing or contacting said subject or at least one other sample obtained from said subject to or with an immuno-stimulant; 
 IIc. determining the level of expression of at least one of ISG15, IFIT1, IFIT2, IFITM3, IFIT3, IFIT5, OAS1, OAS2, OAS3, OASL, HERC5, USP18, RSAD2, MX1, IFI44L, DDX58, UBE1L, UBE2L6, IFI27, IFIH1, TLR7, IRF7, IFI6, STAT1, IFI44, EIF2AK2 and DHX58 genes in said at least one other biological sample of said subject obtained in step IIb; and 
 IId. calculating the rate of change (RC) between the expression value obtained in step (IIa), and the expression value obtained in step (IIc), thereby obtaining the rate of change in the sample RC samp ; 
 IIe. providing a standard curve of the rate of change in the expression of at least one of ISG15, IFIT1, IFIT2, IFITM3, IFIT3, IFIT5, OAS1, OAS2, OAS3, OASL, HERC5, USP18, RSAD2, MX1, IFI44L, DDX58, UBE1L, UBE2L6, IFI27, IFIH1, TLR7, IRF7, IFI6, STAT1, IFI44, EIF2AK2 and DHX58 genes in subjects treated with said immuno-stimulant; 
 IIf. Obtaining a maximal rate of change value RC max  and a minimal rate of change RC min  value from said standard curve of (IIe); and 
 IIg. Calculating the M value of said sample, wherein M=[(RC samp −RC min )/(RC max −RC min )], thereby obtaining an M value of said subject; or 
   III. A dynamic analysis comprising:
 IIIa. determining the level of expression of at least one of ISG15, IFIT1, IFIT2, IFITM3, IFIT3, IFIT5, OAS1, OAS2, OAS3, OASL, HERC5, USP18, RSAD2, MX1, IFI44L, DDX58, UBE1L, UBE2L6, IFI27, IFIH1, TLR7, IRF7, IFI6, STAT1, IFI44, EIF2AK2 and DHX58 genes in a biological sample of said subject, to obtain an expression value in said sample, wherein said sample is obtained prior the initiation of said treatment with said medicament; 
 IIIb. determining the level of expression of at least one ISG15, IFIT1, IFIT2, IFITM3, IFIT3, IFIT5, OAS1, OAS2, OAS3, OASL, HERC5, USP18, RSAD2, MX1, IFI44L, DDX58, UBE1L, UBE2L6, IFI27, IFIH1, TLR7, IRF7, IFI6, STAT1, IFI44, EIF2AK2 and DHX58 genes in at least one other biological sample of said subject, wherein said at least one other sample is obtained after the initiation of said treatment; 
 IIIc. calculating the rate of change between the expression value obtained in step (IIIa), and the expression value obtained in step (IIIb), thereby obtaining the rate of change in the sample RC samp ; 
 IIId. providing a predetermined standard curve of the rate of change in the expression of at least one of ISG15, IFIT1, IFIT2, IFITM3, IFIT3, IFIT5, OAS1, OAS2, OAS3, OASL, HERC5, USP18, RSAD2, MX1, IFI44L, DDX58, UBE1L, UBE2L6, IFI27, IFIH1, TLR7, IRF7, IFI6, STAT1, IFI44, EIF2AK2 and DHX58 genes in subjects suffering from the same disorder that were treated with said medicament; 
 IIIe. Obtaining a maximal rate of change value RC max  and a minimal rate of change value RC min  from said standard curve of (IId); and 
 IIIf. Calculating the M value of said sample, wherein M=RC samp −RC min )/(RC max −RC min )], thereby obtaining an M value of said subject. 
   
     
     
         3 . The method according to  claim 2 , wherein calculating the value of M1 is performed by the steps of any one of:
 I. Ia. Providing a K value for said disorder;
 Ib. calculating the M1, wherein M1≥1−(1/k), thereby determining the M1 value; and 
   II. IIa. Providing a standard M1 value calculated for a responder population.   
     
     
         4 . The method according to  claim 2 , wherein in steps (a) and (b) the expression of OAS2, HERC5, UPS18, UBE216 and optionally of ISG15 genes is determined. 
     
     
         5 . The method according to  claim 1 , wherein said method is for determining a personalized interferon treatment regimen for a subject suffering from a pathologic disorder. 
     
     
         6 . The method according to  claim 2 , wherein determining the level of expression of at least one of said ISG15, IFIT1, IFIT2, IFITM3, IFIT3, IFIT5, OAS1, OAS2, OAS3, OASL, HERC5, USP18, RSAD2, MX1, IFI44L, DDX58, UBE1L, UBE2L6, IFI27, IFIH1, TLR7, IRF7, IFI6, STAT1, IFI44, EIF2AK2 and DHX58 genes in a biological sample of said subject is performed by the step of contacting detecting molecules specific for said genes with a biological sample of said subject, or with any nucleic acid or protein product obtained therefrom, and wherein said detecting molecules are selected from isolated detecting nucleic acid molecules and isolated detecting amino acid molecules. 
     
     
         7 . The method according to  claim 6 , wherein said nucleic acid detecting molecule comprises isolated oligonucleotide/s, each oligonucleotide specifically hybridizes to a nucleic acid sequence of said at least one of ISG15, IFIT1, IFIT2, IFITM3, IFIT3, IFIT5, OAS1, OAS2, OAS3, OASL, HERC5, USP18, RSAD2, MX1, IFI44L, DDX58, UBE1L, UBE2L6, IFI27, IFIH1, TLR7, IRF7, IFI6, STAT1, IFI44, EIF2AK2 and DHX58 genes and optionally, to a control reference gene, and wherein said detecting molecule is at least one of a pair of primers, at least one primer, nucleotide probes or any combinations thereof. 
     
     
         8 . The method according to  claim 1 , wherein said subject is suffering from an immune-related disorder, and wherein said immune-related disorder is any one of an infectious condition, an autoimmune disease, and a proliferative disorder. 
     
     
         9 . The method according to  claim 8 , wherein said subject is suffering from an infectious condition caused by any one of (Hepatitis C virus) HCV, dengue virus, influenza, poliovirus, HIV (human immune deficiency virus) and West Nile virus (WNV) infection. 
     
     
         10 . The method according to  claim 8 , wherein said subject is suffering from Multiple sclerosis (MS). 
     
     
         11 . The method according to  claim 8 , wherein said subject is suffering from Rheumatoid Arthritis (RA), and wherein said genes are at least one of IFIT1, IFITM3, IFIT3, OAS1, OAS3, HERC5, RSAD2, MX1, IFI44L, IFI6, IFI44 and DDX58 genes. 
     
     
         12 . The method according to  claim 2 , wherein said immuno-stimulant is any one of a synthetic double stranded RNA (poly ICLC), yellow fever (YF) vaccine 17D (YF17D). 
     
     
         13 . A kit for determining and/or optimizing a personalized treatment regimen for a subject suffering from a pathologic disorder comprising:
 a. detecting molecules specific for determining the level of expression of at least one of ISG15, IFIT1, IFIT2, IFITM3, IFI44L, IFIT3, IFIT5, OAS1, OAS2, OAS3, OASL, HERC5, USP18, RSAD2, MX1, IFI44L, DDX58, UBE1L, UBE2L6, IFI27, IFIH1, TLR7, IRF7, IFI6, STAT1, IFI44, EIF2AK2 and DHX58 genes in a biological sample, wherein said detecting molecules are selected from isolated detecting nucleic acid molecules and isolated detecting amino acid molecules;   b. means for calculating the M value of a tested subject, wherein said value indicates the ability of said subject to eliminate said disorder;   c. means for calculating the value of M1 or a standard M1 value calculated for a responder population, said M1 value indicates the minimal ability required for eliminating said disorder; and   d. means for calculating the dose A and number B of administrations of said dose A to obtain an amount C of said medicament required for said subject.   
     
     
         14 . The kit according to  claim 13 , wherein means for calculating the value of M comprise at least one of:
 I. means for static analysis comprising:
 Ia. detecting molecules specific for determining the level of expression of ISG15, IFIT1, IFIT2, IFITM3, IFI44L, IFIT3, IFIT5, OAS1, OAS2, OAS3, OASL, HERC5, USP18, RSAD2, MX1, IFI44L, DDX58, UBE1L, UBE2L6, IFI27, IFIH1, TLR7, IRF7, IFI6, STAT1, IFI44, EIF2AK2 and DHX58 genes in a biological sample for determining an expression value Ex samp  in said sample; 
 Ib. a standard curve of expression values of subjects suffering from the same pathologic disorder or predetermined maximal expression value Ex max  and a minimal expression value Ex min  calculated from said standard curve; and 
 Ic. a formula for calculating M value, wherein said formula is M=[(Ex samp −Ex min )/(Ex max −Ex min )]; 
   II. means for an induced dynamic analysis comprising:
 IIa. detecting molecules specific for determining the level of expression of ISG15, IFIT1, IFIT2, IFITM3, IFI44L, IFIT3, IFIT5, OAS1, OAS2, OAS3, OASL, HERC5, USP18, RSAD2, MX1, IFI44L, DDX58, UBE1L, UBE2L6, IFI27, IFIH1, TLR7, IRF7, IFI6, STAT1, IFI44, EIF2AK2 and DHX58 genes in a biological sample for determining an expression value Ex samp  in said sample before and after stimulation of said subject with an immuno-stimulant, and for calculating the rate of change RC samp  in the expression value Ex samp  of said sample before and after stimulation; 
 IIb. an immuno-stimulant; 
 IIc. a standard curve of the rate of change in the expression of at least one of ISG15, FIT1, IFIT2, IFITM3, IFI44L, IFIT3, IFIT5, OAS1, OAS2, OAS3, OASL, HERC5, USP18, RSAD2, MX1, IFI44L, DDX58, UBE1L, UBE2L6, IFI27, IFIH1, TLR7, IRF7, IFI6, STAT1, IFI44, EIF2AK2 and DHX58 genes in subjects treated with said immuno-stimulant, or predetermined maximal rate of change value RC max  and a minimal rate of change RC min  value calculated from said standard curve; and 
 IId. a formula for calculating said M value, wherein said formula is M=[(RC samp −RC min )/(RC max −RC min )]; and 
   III. means for a dynamic analysis comprising:
 IIIa. detecting molecules specific for determining the level of expression of ISG15, IFIT1, IFIT2, IFITM3, IFI44L, IFIT3, IFIT5, OAS1, OAS2, OAS3, OASL, HERC5, USP18, RSAD2, MX1, IFI44L, DDX58, UBE1L, UBE2L6, IFI27, IFIH1, TLR7, IRF7, IFI6, STAT1, IFI44, EIF2AK2 and DHX58 genes in a biological sample for determining an expression value Ex samp  in said sample before and after treatment of said subject with said medicament, and for calculating the rate of change RC samp  in the expression value Ex samp  of said sample; 
 IIIb. a predetermined standard curve of the rate of change in the expression of at least one of ISG15, IFIT1, IFIT2, IFITM3, IFI44L, IFIT3, IFIT5, OAS1, OAS2, OAS3, OASL, HERC5, USP18, RSAD2, MX1, IFI44L, DDX58, UBE1L, UBE2L6, IFI27, IFIH1, TLR7, IRF7, IFI6, STAT1, IFI44, EIF2AK2 and DHX58 genes in subjects suffering from the same disorder and treated with said medicament, or predetermined maximal rate of change value RC max  and minimal rate of change value RC min  calculated from said standard curve; and 
 IIIc. a formula for calculating said M value, wherein said formula is M=[(RC samp −RC min )/(RC max −RC min )]; 
   and wherein means for calculating the value of M1 comprise:   a. a predetermined K value of said disorder;   b. a formula for calculating said M1 value, wherein said formula is M1≥1−(1/k).   
     
     
         15 . The kit according to  claim 13 , wherein said nucleic acid detecting molecule comprises isolated oligonucleotides, each oligonucleotide specifically hybridizes to a nucleic acid sequence of said at least one of ISG15, IFIT1, IFIT2, IFITM3, IFI44L, IFIT3, IFIT5, OAS1, OAS2, OAS3, OASL, HERC5, USP18, RSAD2, MX1, IFI44L, DDX58, UBE1L, UBE2L6, IFI27, IFIH1, TLR7, IRF7, IFI6, STAT1, IFI44, EIF2AK2 and DHX58 genes and optionally, to a control reference gene, and wherein said detecting molecule is at least one of a pair of primers, at least one primer, nucleotide probes or any combinations thereof. 
     
     
         16 . The kit according to  claim 13 , wherein said subject is suffering from an infectious condition caused by any one of HCV, dengue virus, influenza, poliovirus, HIV and WNV infection. 
     
     
         17 . The kit according to  claim 13 , wherein said subject is suffering from Multiple sclerosis (MS). 
     
     
         18 . The kit according to  claim 13 , wherein said subject is suffering from Rheumatoid Arthritis (RA) and wherein said kit comprises detecting molecules specific for determining the level of expression of at least one of IFIT1, IFITM3, IFIT3, OAS1, OAS3, HERC5, RSAD2, MX1, IFI44L, IFI6, IFI44 and DDX58 genes. 
     
     
         19 . The kit according to  claim 13 , wherein said immuno-stimulant is any one of a synthetic double stranded RNA (poly ICLC), yellow fever (YF) vaccine 17D (YF17D). 
     
     
         20 . A computer software product for determining and/or optimizing a personalized treatment regimen for a subject suffering from a pathologic disorder, the product comprising a computer readable medium in which program instructions are stored, which instructions, when read by a computer, cause the computer to
 a. Calculate and/or determine the value of M, wherein said value indicates the ability of said subject to eliminate said disorder;   b. Determine the value of M1, said value indicates the minimal ability required for eliminating said disorder;   c. calculate the dose A and number B of administrations of said dose A to obtain an amount C required for said subject having said M determined/calculated in step (a), from predetermined dose A1 and number B1 of administrations of said dose, using the formula of A=A/(M1/M) and B=B1*(M1/M).