GENETIC MARKERS PREDICTIVE OF RESPONSE TO GLATIRAMER ACETATE
This application claims the priority of U.S. Provisional Application
No. 61/893,807, filed October 21, 2013, U.S. Provisional Application
No. 62/048,127, filed September 9, 2014, and U.S. Provisional
5 Application No. 62/048,641, filed September 10, 2014, the contents
of which are hereby incorporated by reference.
Throughout this application various publications are referenced.
The disclosures of these publications in their entireties are hereby
10 incorporated by reference into this application in order to more
fully describe the state of the art to which this invention
pertains.
BACKGROUND OF THE INVENTION
15 Multiple Sclerosis
Multiple sclerosis (MS) is a chronic, debilitating autoimmune
disease of the central nervous system (CNS)
remitting (RR) or progressive course
with either relapsingleading
to neurologic
deterioration and disability. At time of initial diagnosis, RRMS is
20 the most common form of the disease ( 1) which is characterized by
unpredictable acute episodes of neurological dysfunction (relapses),
followed by variable recovery and periods of clinical stability. The
vast majority of RRMS patients eventually develop secondary
progressive (SP) disease with or without superimposed relapses.
25 Around 15% of patients develop a sustained deterioration of their
neurological function from the beginning; this form ls called
primary progressive (PP) MS. Patients who have experienced a single
clinical event (Clinically Isolated Syndrome or "CIS") and who show
lesion dissemination on subsequent magnetic resonance imaging (MHI)
30 scans according to McDonald's criteria, are also considered as
having relapsing MS. (2)
With a prevalence that varies considerably around the world, MS is
the most common cause of chronic neurological disability in young
wo 2015/061367 PCT!US2014/061647
- 2 -
adults. (3,4) Anderson et al. estimated that there were about 350,000
physician-diagnosed patients with MS in the United States in 1990
(approx. 140 per 100,000 population). (5) It is estimated that about
2.5 million individuals are affected worldwide. (6) In general, there
5 has been a trend toward an increasing prevalence and incidence of MS
worldwide, but the reasons for this trend are not fully
understood. ( 5)
Current therapeutic approaches consist of i) symptomatic treatment
10 ii) treatment of acute relapses with corticosteroids and iii)
treatment aimed to modify the course of the disease. Currently
approved therapies target the inflammatory processes of the disease.
Most of them are considered to act as immunomodulators but their
mechanisms of action have not been completely elucidated.
15 Immunosuppressants
patients after
or cytotoxic agents are
failure of conventional
also used
therapies.
in some
Several
medications have been approved and clinically ascertained as
efficacious for the treatment of RR-MS; including BETASERON®,
AVONEX® and REBIF®, which are derivatives of the cytokine interferon
20 beta (IFNB), whose mechanism of action in MS is generally attributed
to its immunomodulatory effects, antagonizing pro-inflammatory
reactions and inducing suppressor cells. (7) Other approved drugs for
the treatment of MS include Mitoxantrone and Natalizumab.
25 Glatiramer Acetate
Glatiramer acetate (GA) is
marketed product indicated
relapses in patients with
the active substance in
for reduction of the
RRMS. Its effectiveness
Copaxone®, a
frequency of
in reducing
relapse rate and disability accumulation in RR-MS is comparable to
30 that of other available immunomodulating treatments.(8,9,10)
Glatiramer acetate consists of the acetate salts of synthetic
polypeptides containing four naturally occurring amino acids: Lglutamic
acid, L-alanine, I.-tyrosine and L-lysine. The average
molecular weight of glatiramer acetate is between 5, 000 and 9, 000
35 Daltons. At a daily standard dose of 20 mg, GA is generally well
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- 3 -
tolerated, however response to the drug is variable. In various
clinical trials, GA reduced relapse rates and progression of
disability in patients with RR-MS. The therapeutic effect of GA is
supported by the results of magnetic resonance imaging (MRI)
5 findings from various clinical centers (11), however there are no
validated predictive biomarkers of response to GA treatment.
A possible initial mode of action of GA is associated with binding
to MHC molecules and consequent competition with various myelin
10 antigens for their presentation to T cells. (12) A further aspect of
its mode of action is the potent induction of T helper 2 (Th2) type
cells that presumably can migrate to the brain and lead to in situ
bystander suppression. (13) It has been shown that GA treatment in MS
results in the induction of GA-specific T cells with predominant Th2
15 phenotype both in response to GA and cross-reactive myelin
antigens. (13,14) Furthermore, the ability of GA-specific
infiltrating cells to express anti-inflarrunatory cytokines such as
IL-10 and transforming growth factor-beta (TGF-0) together with
brain-derived neurotrophic factor (BDNF) seem to correlate with the
20 therapeutic activity of GAin EAE. (15,16,17)
25
Clinical experience with GA consists of information obtained from
completed and ongoing clinical trials and from post-marketing
experience. The clinical program includes
placebo-controlled studies in RRMS subjects
three double-blind,
treated with GA 20
mg/day. (18,19,20) A significant reduction in the number of relapses,
compared with placebo, was seen. In the largest controlled study,
the relapse rate was reduced by 32% from 1.98 under placebo to 1.34
under GA 20 mg. GA 20 mg has also demonstrated beneficial effects
30 over placebo on MRI parameters relevant to RRMS. A significant
effect in median cumulative number of Gd-enhancing lesions over 9
months of treatment (11 lesions in the 20 mg group compared to 17
lesions under placebo) was demonstrated.
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- 4 -
The clinical program with GA also includes one double-blind study in
chronic-progressive MS subjects, (21) one double-blind placebocontrolled
study in primary progressive patients, (22) one doubleblind
placebo-controlled study in CIS patients (23) and numerous
5 open-label and compassionate use studies, mostly in RRMS. The
clinical use of GA has been extensively reviewed and published in
the current literature (24,25,26,27).
10
U.S. Patent No. 7,855,176 discloses administering glatiramer acetate
to patients
(RRMS) by
afflicted with relapsing-remitting multiple sclerosis
subcutaneous injection of 0. 5 ml of an aqueous
pharmaceutical solution which contains in solution 20 mg glatiramer
acetate and 20 mg mannitol (34).
15 U.S. Patent Application Publication No. US 2011-0046065 Al discloses
administering glatiramer acetate to patients suffering from
relapsing-remitting multiple sclerosis by three subcutaneous
injections of a therapeutically effective dose of glatiramer acetate
over a period of seven days with at least one day between every
20 subcutaneous injection (35).
Pharmacogenomics
Pharmacogenomics is the methodology which associates genetic
variability with physiological responses to drug. Pharmacogenetics
25 is a subset of pharmacogenomics and is defined as "the study of
variations in DNA sequence as related to drug response" (ICH El5;
fda.gov/downloads/Regulatoryinformation/Guidances/ucml29296.pdf.
Pharmacogenetics focuses on genetic polymorphism in genes related to
drug metabolism, drug mechanism of action, disease type, and side
30 effects. Pharmacogenetics is the cornerstone of Personalized
Medicine which allows the development of more individualized drug
therapies to obtain more effective and safe treatment.
Pharmacogenetics has become a core component of many drug
wo 2015/061367 PCT/US2014/061647
- 5 -
development programs, being used to explain variability in drug
response among subjects in clinical trials, to address unexpected
emerging clinical issues, such as adverse events, to determine
eligibility for a clinical trial (pre-screening) to optimize trial
5 yield, to develop drug-linked diagnostic tests to identify patients
who are more likely or less likely to benefit from treatment or who
may be at risk of adverse events, to provide information in drug
labels to guide physician treatment decisions, to better understand
the mechanism of action or metabolism of new and existing drugs, and
10 to provide better understanding of disease mechanisms.
Generally, Pharmacogenetics analyses are performed in either of two
methodology approaches: Candidate genes research technique, and
Genome Wide Association Study (GWAS). Candidate genes research
15 technique is based on the detection of polymorphism in candidate
genes pre-selected using the knowledge on the disease, the drug mode
of action, toxicology or metabolism of drug. The Genome Wide
Association Study (GWAS) enables the detection of more than 1 M (one
million) polymorphisms across the genome. This approach is used when
2 0 related genes are unknown. DNA arrays used for GWAS can be also
analyzed per gene as in candidate gene approach.
Pharmacogenetic studies
Various pharmacogenetic studies were done in MS patients. For
25 example, a Genome-Wide Association study by Byun et al. (36) focused
on extreme clinical phenotypes in order to maximize the ability to
detect genetic differences between responders and non-responders to
interferon-beta. A multi-analytical approach detected significant
associations between several SNPs and treatment response. Responders
30 and Non-Responders had significantly different genotype frequencies
for SNPs located in many genes, including glypican 5, collagen type
XXV al, hyaluronan proteoglycan link protein, calpastatin, and
neuronal PAS domain protein 3. Other studies used pharmacogenetic
analyses in order to characterize the genomic profile and gene
35 expression profile of IFN responders and non-responders.
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- 6 -
Other pharmacogenetic studies analyzed the genetic background
associated with response to Glatiramer Acetate. For examples, Fusco
C et al (37) assessed a possible relationship between HLA alleles
and response to GA (N=83 RRMS). DRB1*1501 allele frequency was
5 increased in MS patients compared to healthy controls (10.8% vs
2.7%; p= 0.001). In DRB1*1501 carriers the response rate was 81.8%
compared to 39.4% in non-carriers of DRB1*1501 and to 50% in the
whole study population. Grossman et al (38) genotyped HLA-DRB1*1501
and 61 SNPs within a total of 27 other candidate genes, on DNA from
10 two clinical trial cohorts. The study revealed no association
between HLA-DRB1*1501 and response to GA. The results of the study
are disclosed in the international application published as
W02006/116602 (39).
15 Pharmacogenetics is the cornerstone of personalized medicine which
allows the development of more individualized drug therapies to
obtain more effective and safe treatment. Multiple Sclerosis is a
complex disease with clinical heterogeneity. In patients afflicted
with multiple sclerosis or a single clinical attack consistent with
20 multiple sclerosis, the ability to determine the likelihood of
treatment success would be an important tool improving the
therapeutic management of the patients. As the therapeutic options
for MS and CIS increase, the importance of being able to determine
who will respond favorably to therapy and specifically to GA, has
25 become of increasing significance.
wo 20151061367 PCT /US20 14/0ill ll4 7
- 7 -
SUMMARY OF THE :INVENTION
INDEPENDENT EMBODIMENTS
The present invention provides a method for treating a human subject
5 afflicted with multiple sclerosis or a single clinical attack
consistent with multiple sclerosis with a pharmaceutical composition
comprising glatiramer acetate and a pharmaceutically acceptable
carrier, comprising the steps of:
(i) determining a genotype of the subject at a location
10 corresponding to the location of one or more single
nucleotide polymorphisms (SNPs) selected from the group
consisting of: kgpl0090631, kgpl009249, kgpl0152733,
15
20
25
30
35
kgpl0224254,
kgpl0404633,
kgpl0558725,
kgpl0619195,
kgpl0679353,
kgpl0922969,
kgpl098237,
kgplll41512.
kgpll2 81589.
kgpll407560,
kgpll543962,
kgpll686146.
kgpl0305127,
kgpl0412303,
kgpl0564659,
kgpl0620244,
kgpl0788130'
kgpl0948564,
kgpll002881,
kgpll206453,
kgpll285862,
kgpll453406,
kgpll580695,
kgpll7024 74.
kgpl0351364.
kgpl0523170,
kgpl0591989,
kgpl0632945,
kgpl0826273,
kgpl096704 6.
kgpll010680'
kgpll210903.
kgpll32862 9'
kgpll467007,
kgpll627530'
kgpll711524.
kgpl0372946,
kgpl054273,
kgp105944l4,
kgpl0633631,
kgpl091 0719'
kgpl0974833,
kgpll0773 73'
kgpll24492,
kgpl1356379'
kgpll514107.
kgpll633966,
kgpll768533'
kgpll804835, kgpll843177, kgpl2008955, kgpl2083934,
kgpl2182745, kgpl2230354, kgpl224440, kgpl2371757, kgpl24162,
kgpl2426624, kgpl2557319. kgpl285441, kgpl3161760,
kgpl3 55977. kgpl3 71881. kgpl53 90522. kgpl683448' kgpl6887 52'
kgpl69 962 8' kgpl753 445. kgpl779254' kgpl78 6079. kgpl83 7977 4'
kgpl8432055. kgpl852 5257' kgpl912 531, kgpl95 6 8724'
kgp20163979, kgp2023214, kgp2045074, kgp20478926, kgp2092817,
kgp21171930,
kgp22793211,
kgp2299675,
kgp23737989,
kgp2245775,
kgp22811918,
kgp23298674,
kgp2388352,
kgp2262166,
kgp22823022,
kgp2356388,
kgp2391411,
kgp22778566,
kgp2282938,
kgp23672937,
kgp2413lll6,
kgp24415534, kgp2446153, kgp2451249, kgp2465184, kgp24729706,
wo 2015/061367 PCT /US2014/0616-t 7
- 8 -
kgp24753470, kgp25191871, kgp25216186, kgp25543811,
kgp2592129L kgp25952891, kgp26026546, kgp26271158,
kgp2638591, kgp26528455, kgp26533576, kgp2688306,
kgp26995430, kgp270001, kgp2709692, kgp2715873, kgp27500525,
5 kgp27571222, kgp27640141, kgp2788291, kgp279772, kgp28532436,
kgp28586329, kgp28687699, kgp28817122, kgp2923815,
kgp2936752L kgp293787, kgp2958113' kgp2 959751' kgp2971 78,
kgp29794723, kgp30282494, kgp3048169, kgp304921, kgp3182607,
kgp3202939, kgp3205849, kgp32183 51' kgp3267884, kgp3276689,
10 kgp33746L kgp3418770, kgp3450875, kgp345301, kgp347735L
kgp3496814, kgp355027, kgp355723, kgp3593828, kgp3598409,
kgp3651767, kgp3669685, kgp3730395, kgp3812034, kgp38541BO,
kgp3933330, kgp3951463, kgp3984567, kgp3991733' kgp4011779'
kgp4056892, kgp4096263, kgp4127859, kgp4155998, kgp4162414,
15 kgp4223880, kgp4346717, kgp4370912, kgp4418535, kgp442079L
kgp4479467, kgp4524468, kgp4543470, kgp4559907, kgp4573213,
kgp4634875, kgp4705854, kgp4734301, kgp4755147, kgp4812831,
kgp4842590, kgp485316, kgp487328, kgp4898179, kgp500201L
kgp5014707, kgp5017029, kgp5053636, kgp5068397, kgp5121BO,
20 kgp5144181, kgp5159037, kgp5216209, kgp5292386, kgp5334779,
kgp5388938, kgp5409955, kgp5440506, kgp5441587, kgp5483926,
kgp55646, kgp5564995, kgp5579170, kgp5680955, kgp5869992,
kgp5908616, kgp6023196, kgp6032617, kgp6038357, kgp6076976,
kgp6091119' kgp61273 71' kgp61811, kgp6190988, kgp6214 3 51'
25 kgp6228750, kgp6236949, kgp6469620, kgp6505544, kgp6507761'
kgp65253 4' kgp6539666, kgp6567154, kgp65994 3 8' kgp6603796,
kgp6666134, kgp6700691, kgp6737096, kgp6768546, kgp6772915'
kgp683 5138' kgp6959492, kgp6996560, kgp7059449, kgp7063887,
kgp7077322, kgp7092772, kgp7117398, kgp712137 4' kgp7178233,
30 kgp7181058, kgp7186699' kgp7189498, kgp7242489, kgp7331172'
kgp7416024, kgp7481870, kgp7506434, kgp7521990, kgp759150,
kgp767200, kgp7714238, kgp7730397, kgp7747883, kgp7792268,
kgp7802182, kgp7804623, kgp7924485, kgp8030775, kgp8036704,
kgp804 6214' kgp8106690, kgp8107491' kgp8110667' kgp8169636,
35 kgp8174785, kgp8178358, kgp8183049, kgp8192 54 6' kgp8200264,
kgp8303520, kgp8335515, kgp8372910, kgp841428, kgp843 7 9 6l,
wo 2015/061367 PCT/US2014/06164 7
- 9 -
kgp8440036, kgp85534, kgp8599417, kgp86 02316' kgp8615910,
kgp8767692, kgp8777935, kgp8793915, kgp8796185, kgp8817856,
kgp8869954, kgp8990121, kgp9018750, kgp9071686' kgp9078300,
kgp9320791, kgp9354462, kgp9354820, kgp9368119' kgp9410843,
5 kgp9421884, kgp9450430, kgp9530088, kgp9551947, kgp9601362,
kgp9627338, kgp9627406, kgp9669946' kgp9699754, kgp971582,
kgp97310, kgp974569, kgp9795732, kgp9806386, kgp9854133,
kgp9884626, rs10049206, rs10124492, rs10125298, rs10162089,
rs10201643, rs10203396, rs10251797, rs10278591, rs10489312,
10 rs10492882, rs10498793, rs10501082, rs10510774, rs10512340,
rsl079303, rs10815160, rsl0816302, rs10841322, rs10841337,
rs10954782, rsl1002051, rsl1022778, rs11029892, rsll029907,
rsl1029928, rsl1083404, rsll085044, rs11136970, rs1114 7439,
rs11192461, rsl1192469, rsll559024, rs1157449, rs11648129,
15 rsl1691553, rs12013377, rs12494712, rs12943140, rs13002663,
rs13394010, rs13415334, rs13419758, rs1380706, rs1387768,
rs1410779, rs1478682, rs1508102, rs1532365, rs1544352,
rs1545223, rs1579771, rs1604169, rs1621509, rs1644418,
rs16886004, rs16895510, rs16901784, rs16927077, rs16930057,
20 rs17029538, rs17224858, rs17238927, rs17329014, rs17400875,
rs17449018, rs17577980, rs1763879L rs1858973, rs1886214,
rs1894406, rs1894407, rs1894408, rs196295, rs196341,
rs196343, rs197523, rs1979992, rs1979993, rs2043136,
rs2058742, rs2071469, rs2071470, rs2071472, rs2074037,
25 rs2136408, rs2139612, rs2175121, rs2241883, rs2309760,
rs23259ll, rs241435, rs241440, rs241442, rs241443, rs241444,
rs241445, rs241446, rs241447, rs241449, rs241451, rs241452,
rs241453, rs241454, rs241456, rs2453478, rs2598350,
rs2621321, rs2621323, rs2660214, rs281683 8, rs2824070,
30 rs2839117, rs2845371, rs2857101, rs2857103, rs2857104,
rs2926455, rs2934491, rs3135388, rs3218328, rs343087,
rs343092, rs3767955, rs3792135, rs3799383, rs3803277,
rs3815822, rs3818675, rs3829539, rs3885907, rs3899755,
rs4075692, rs4143493, rs419132, rs423239, rs4254166,
35 rs4356336, rs4360791, rs4449139, rs4584668, rs4669694,
rs4709792, rs4738738, rs4769060, rs4780822, rs4782279,
5
10
15
20
25
30
35
wo 2015/061367 PCT/US2014/0616-t7
rs4822644,
rs543122,
rs6497396,
rs6840089,
rs7024953,
rs7187976,
rs7348267,
rs759458,
rs7725112,
rs7864679,
rs484482,
rs6032205,
rs6535882,
rs6845927,
rs7028906,
rs7191155,
rs7496451,
rs7666442,
rs7844274,
rs7928078,
- 10 -
rs4894701,
rs6032209,
rs6687976,
rs6895094,
rs7029123,
rs720176,
rs7524868,
rs7670525,
rs7850,
rs7948420,
rs8053136, rs8055485, rs823829,
rs931570, rs9346979, rs937636L
rs9508832, rs950928, rs9579566,
rs9671124, rs9671182, rs9817308,
rs5024722,
rs6110157,
rs6718758,
rs6899068,
rs7062312,
rs721 7872,
rs7563131,
rs7672014,
rs7860748,
rs8035826,
rs858341,
rs9393727,
rs9597498,
rs9834010,
rs502530,
rs623011,
rs6835202,
rs7020402,
rs714342,
rs7228827,
rs7579987,
rs7677801,
rs7862565,
rs8050872,
rs9315047,
rs95012/.4,
rs9670531,
rs9876830,
rs9913349, rs9931167 and rs9931211 (hereinafter Group 1),
( ii) identifying the subject as a predicted responder to
glatiramer acetate if the genotype of the subject contains
one or more A alleles at the location of kgp10152733,
kgp10224254,
kgp10404633,
kgp10619195,
kgpll002881,
kgpll514107'
kgp11768533,
kgp10305127,
kgp10561659,
kgp10620244,
kgpll285862,
kgp11627530,
kgp11804835,
kgp103 513 64'
kgp10591989'
kgp10633631,
kgpll328629'
kgp11702474,
kgp12083934,
kgp10372946,
kgp10594414,
kgp10974833,
kgpl1407560,
kgpll711524,
kgp12182745,
kgp12230354, kgp1224440, kgp124162, kgp12557319, kgp137188 L
kgp1699628, kgp1753445' kgp1779254' kgp1786079' kgp18379774'
kgp18525257,
kgp21171930,
kgp24753470,
kgp26026546,
kgp20163979'
kgp2262166,
kgp25191871,
kgp26533576,
kgp2023214,
kgp22778566'
kgp25216186,
kgp27500525,
kgp20478926,
kgp/.465184,
kgp25952891,
kgp27571222,
kgp28532436, kgp28586329, kgp28817122, kgp2958113,
kgp29794723, kgp30282494, kgp30492L kgp3205849, kgp3218351,
kgp3276689, kgp337461, kgp345301, kgp355027, kgp355723,
kgp3593828, kgp3812034, kgp3951463, kgp4162414, kgp4223880,
kgp441853 5'
kgp4842590,
kgp4543470, kgp4573213,
kgp485316, kgp5068397,
kgp4634875,
kgp5334779,
kgp4.155147'
kgp5483926,
5
10
15
20
25
30
35
wo 2015/061367 PCT/US20 14/06164 7
kgp55649951
kgp60769761
kgp62287501
kgp66661341
- 11 -
kgp58699921 kgp59086161 kgp60326171
kgp6091119 1 kgp61273711 kgp618111
kgp62369491 kgp64696201 kgp65055441
kgp67006911 kgp67729151 kgp69594921
kgp60383571
kgp62143 51,
kgp6507761 1
kgp70773221
kgp7117398 1 kgp7178233 1 kgp7186699 1 kgp7506434~ kgp7S91501
kgp77303971 kgp78021821 kgp78046231 kgp79244851
kgp80367041 kgp80462141 kgp81066901 kgp81106671
kgp82002641
kgp87939151
kgp9 3 68119 1
kgp96699461
kgp83729101 kgp8414281 kgp86023161
kgp87961851 kgp89901211 kgp90187501
kgp94108431 kgp94504301 kgp95300881
kgp973101 kgp9745691 kgp98063861
kgp80307751
kgp81783581
kgp86159101
kgp93544621
kgp 9 6 2 7 3 3 8 1
kgp9 884 62 61
rsl0049206 1 rsl0124492 1 rs10125298 1 rsl01620891 rsl0203396 1
rsl0251797 1 rsl0278591~ rs10489312~ rsl0492882~ rsl0498793~
rsl0501082 1 rsl0510774 1 rs10512340~ rsl0815160~ rsl08163021
rsl0841337 1 rsl1029892~ rs11029928 1 rsll192469~ rs11559024~
rsl1648129 1 rsl2013377~ rsl3394010~ rs134153341 rs1478682~
rs1544352 I rs1545223 I rsl604169 I rs1621509 I rs1644418 I
rsl7029538 1 rsl74008751 rs17449018 1 rs17577980~
rsl8944061 rs1894407 I rs197523~ rs2058742~
rs20714721 rs21396121 rs2241883~ rs23097601
rs241442~ rs241444~ rs241445 1 rs241446 1 rs241449 1
rs241456 1
rs2857103 1
rs3792135 1
rs4232391
rs4782279 1
rs64973961
rs7028906 1
rs7201761
rs7666442 1
rs7862565 1
rs823829 1
rs9597498 1
rs24534781 rs2660214 1
rs29264551 rs343087 I
rs38295391
rs42541661
rs5024722 1
rs6845927 1
rs70291231
rs7228827 I
rs76705251
rs79484201
rs9315047 1
rs9670531 1
rs3899755 1
rs4356336 1
rs6032209 1
rs6895094~
rs7062312 1
rs7496451 1
rs7677801 1
rs8035826 1
rs9501224 1
rs9671124 I
rs2824070 1
rs343092 1
rs4075692 1
rs45846681
rs6110157 I
rs6899068 1
rs7187976~
rs7563131 1
rs7725112 I
rs8053136~
rs9508832~
rs9817308 1
rs9876830 or rs9931211 (hereinafter Group 2) 1
rs1858973~
rs20714691
rs241440~
rs241453 I
rs2845371 I
rs3767955~
rs4143493~
rs4780822~
rs623011,
rs7024953~
rs7191155 I
rs759458 1
rs78501
rs80554851
rs950928 1
rs9834010~
one or more C alleles at the location of kgp10910719 1
kgp110773731 kgpl1453406 1 kgp124266241 kgp20450741
5
10
15
20
25
30
35
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kgp228119181 kgp232986741 kgp27096921 kgp286876991
kgp34968141 kgp36696851 kgp37303951 kgp40568921 kgp43709121
kgp50536361 kgp52162091 kgp52923861 kgp60231961 kgp6525341
kgp70594491 kgp71894981 kgp75219901 kgp77922681 kgp83035201
kgp9320791 1 kgp9795732 1 rsl02016431 rs11022778~ rslll369701
rs11147439 1 rsll691553 1 rs1579771 1 rsl6901784 I rs213 6408 I
rs2325911~ rs241443 I rs28571041 rs3803277 1 rs3885907 I
rs4738738 1 rs4894701, rs502530 I rs6032205 1 rs6687976 I
rs6718758 1 rs6835202 1 rs714342 1 rs75248681 rs78442741
rs9393727 or rs9671182 (hereinafter Group 3) I
one or more G alleles at the location of kgpl0090631 1
kgpl0092491 kgpl04123031 kgpl05231701 kgpl0542731
kgpl05587251
kgpl08262731
kgpl0982371
kgpll2109031
kgp11467007 1
kgpll6861461
kgpl06329451
kgpl09229691
kgpll010680 1
kgpll24492 1
kgpll543962 1
kgpll843177 1
kgpl06793531
kgpl09485641
kgplll415121
kgpll281589 1
kgp11580695 1
kgpl20089551
kgpl 07 8813 01
kgpl0967046 1
kgpll206453 1
kgp113563791
kgp11633966 1
kgpl2371757 1
kgpl2 85441, kgpl3161 7 601 kgpl3 55 9771 kgpl5390 522 1 kgpl68344 81
kgpl6887521 kgpl9125311 kgpl9568724 1 kgp2092817 1 kgp2245775l
kgp227932111 kgp228230221 kgp22829381 kgp22996751 kgp23563881
kgp236729371 kgp237379891 kgp23883521 kgp23914111
kgp241311161 kgp244155341 kgp24461531 kgp24512491
kgp247297061 kgp255438111 kgp259212911 kgp262711581
kgp2 63 85911 kgp26528455 1 kgp2 6883061 kgp2 69 9 543 01 kgp27 0001,
kgp27158731 kgp276401411 kgp27882911 kgp29238151 kgp293675211
kgp2937871 kgp29597511 kgp2971781 kgp30481691 kgp31826071
kgp32029391 kgp32678841 kgp34187701
kgp35984091 kgp36517671 kgp38541801
kgp40117791 kgp40962631 kgp41278591
kgp34508751
kgp39333301
kgp41559981
kgp44207911 kgp44794671 kgp45244681 kgp45599071
kgp47343011 kgp48128311 kgp4873281 kgp48981791
kgp3477351,
kgp39845671
kgp43467171
kgp47058541
kgp50020111
kgp50147071 kgp50170291 kgp5121801 kgp51441811 kgp51590371
kgp53889381 kgp54099551 kgp54405061 kgp54415871 kgp556461
kgp55791701 kgp56809551 kgp61909881 kgp65396661 kgp65671541
kgp65994381 kgp66037961 kgp67370961 kgp67685461 kgp68351381
5
10
15
20
25
30
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kgp69965601 kgp70638871 kgp70927721 kgp7121374 1 kgp71810581
kgp7331172 1 kgp74160241 kgp74818701 kgp7672001 kgp771423 81
kgp77478831 kgp81074911 kgp8169 63 61 kgp81747851 kgp81830491
kgp81925461 kgp83355151 kgp8437961, kgp844003 61 kgp855341
kgp85994171 kgp87676921 kgp87779351 kgp88178561 kgp88699541
kgp90716861 kgp90783001 kgp93548201 kgp94218841 kgp95519471
kgp96013621 kgp96274061 kgp96997541 kgp971582 1 kgp9854133 1
rs10793031 rs10841322 1 rs10954782~ rsll002051, rs11029907 I
rs11083404~ rsll085044 1 rsll192461, rsll574491 rs12494712~
rs129431401 rs130026631 rs134197581 rsl380706 1 rs13877681
rs14107791 rs15081021 rs1532365 1 rs168860041 rs16895510 1
rs169270771 rs169300571 rs17224858 1 rs17238927~ rs173290141
rs176387911 rs1886214 1 rs18944081 rs196295 1 rs196341,
rs1963431 rs1979992 1 rs19799931 rs20431361 rs20714701
rs2074037 I rs21751211 rs2414351 rs2414471 rs241451, rs241452,
rs241454~ rs25983601 rs26213211 rs2621323, rs281683 8,
rs2839117 I rs28571011 rs2934491, rs31353881 rs3218328,
rs37993831 rs38158221 rs3818675, rs419132, rs4360791,
rs4449139 I rs4669694 1 rs47097921 rs4769060, rs4822644,
rs484482~ rs5431221 rs6535882 1 rs6840089, rs7020402,
rs7217872~ rs73482671 rs75799871 rs7672014~ rs7860748,
rs7864679~ rs7928078 1 rs80508721 rs858341, rs931570 1
rs93469791 rs9376361, rs95795661 rs9913349 or rs9931167
(hereinafter Group 4)1 or
one or more T alleles at the location of kgp18432055,
kgp279772~ kgp3991733 or kgp7242489; and
(iii) administering the pharmaceutical composition comprising
glatiramer acetate and a pharmaceutically acceptable carrier
to the subject only if the subject is identified as a
predicted responder to glatirarner acetate.
The present invention also provides a method of identifying a human
subject afflicted with multiple sclerosis or a single clinical
attack consistent with multiple sclerosis as a predicted responder
or as a predicted non-responder to glatirarner acetate, the method
35 comprising determining the genotype of the subject at a location
corresponding to the location oE one or more single nucleotide
5
10
15
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- 14 -
polymorphisms (SNPs) selected from the group consisting of Group 1'
and identifying the human subject as a predicted responder to
glatirarner acetate if the genotype of the subject contains
one or more A alleles at the location of Group 2,
one or more c alleles at the location of Group 3'
one or more G alleles at the location of Group 4, or
one or more •r alleles at the location of kgp18432055,
kgp279772, kgp3991733 or kgp7242489,
or identifying the human subject as a predicted non-responder
to glatirarner acetate if the genotype of the subject contains
no A alleles at the location of Group 2'
no c alleles at the location of Group 3,
no G alleles at the location of Group 4, or
no T alleles at the location of kgp18432055, kgp279772,
kgp3991733 or kgp7242489.
'l'he present invention also provides a kit for identifying a human
subject afflicted with multiple sclerosis or a single clinical
20 attack consistent with multiple sclerosis as a predicted responder
or as a predicted non-responder to glatirarner acetate, the kit
comprising at least one probe specific for the location of a SNP
selected from the group consisting of Group 1.
25 'l'he present invention also provides a kit for identifying a human
subject afflicted with multiple sclerosis or a single clinical
attack consistent with multiple sclerosis as a predicted responder
or as a predicted non-responder to glatiramer acetate, the kit
comprising at least one pair of PCR primers designed to amplify a
30 DNA segment which includes the location of a SNP selected from the
group consisting of Group 1.
'l'he present invention also provides a kit for identifying a human
subject afflicted with multiple sclerosis or a single clinical
35 attack consistent with multiple sclerosis as a predicted responder
or as a predicted non-responder to glatirarner acetate, the kit
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comprising a reagent for performing a method selected from the group
consisting of restriction fragment length polymorphism (RFLP)
analysis, sequencing, single strand conformation polymorphism
analysis (SSCP), chemical cleavage of mismatch (CCM), gene chip and
5 denaturing high performance liquid chromatography (DHPLC) for
determining the genotype of the subject at a location corresponding
to the location of at least one SNP selected from the group
consisting of Group 1.
10 The present invention also provides a kit for identifying a human
subject afflicted with multiple sclerosis or a single clinical
attack consistent with multiple sclerosis as a predicted responder
or as a predicted non-responder to glatiramer acetate, the kit
comprising reagents for TaqMan Open Array assay designed for
15 determining the genotype of the subject at a location corresponding
to the location of at least one SNP selected from the group
consisting of Group 1.
The present invention also provides a kit for
subject afflicted with multiple sclerosis or
identifying a human
a single clinical
20 attack consistent with multiple sclerosis as a predicted responder
or as a predicted non-responder to glatiramer acetate, the kit
comprising
a) at least one probe specific for a location corresponding to
the location of at least one SNP;
25 b) at least one pair of PCR primers designed to amplify a DNA
segment which includes a location corresponding to the
location of at least one SNP;
c) at least one pair of PCR primers designed to amplify a DNA
segment which includes a location corresponding to the
30 location of at least one SNP and at least one probe speci fie
for a location corresponding to the location of at least one
SNP;
35
d) a reagent for performing a method selected from the group
consisting of restriction fragment length polymorphism (RFLP)
analysis, sequencing, single strand conformation polymorphism
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analysis (SSCP), chemical cleavage of mismatch (CCM), gene
chip and denaturing high performance liquid chromatography
(DHPLC) for determining the identity of at least one SN?; or
e) reagents for TaqMan Open Array assay designed for determining
5 the genotype at a location corresponding to the location of at
least one SNP,
wherein the at least one SNP is selected from the group
consisting of Group 1.

What is claimed is:
1. A method for treating a human subject afflicted with multiple
sclerosis or a single clinical attack consistent with multiple
sclerosis with a pharmaceutical composition comprising glatiramer
acetate and a pharmaceutically acceptable carrier, comprising the
steps of:
(i) determining a genotype of the subject at a location
corresponding to the location of one or more single
nucleotide polymorphisms (SNPs) selected from the group
consisting of: kgp10090631, kgp1009249, kgp10152733,
kgpl0224254,
kgp10404633,
kgp10558725,
kgp10619195,
kgp10679353,
kgpl0922969,
kgp1098237,
kgp11141512 1
kgp11281589,
kgpl1407560,
kgpl1543962,
kgp11686146,
kgpl180483 51
kgp10305127,
kgp10412303,
kgp10564659,
kgp10620244,
kgp10788130,
kgp10948564,
kgp11002881,
kgpl1206453 1
kgpl1285862 1
kgpl1453406,
kgpll580695,
kgp11702474,
kgpl1843177 1 (ii) identifying the subject as a predicted responder to
glatiramer acetate if the genotype of the subject contains
one or more A alleles at the location of kgpl01527331
kgpl02242541 kgpl03051271 kgpl0351364, kgpl03729461
kgpl04046331 kgpl05646591 kgpl0591989, kgpl05944141
kgpl06191951 kgpl06202441 kgpl06336311 kgpl09748331 (iii) administering
comprising glatiramer
acceptable carrier to
the pharmaceutical composition
acetate and a pharmaceutically
the subject only if the subject is
identified as a predicted responder to glatiramer acetate.
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2. The method of claim 1, wherein step (i) further comprises
determining a genotype of the subject at a location corresponding
to the location of one or more single nucleotide polymorphisms
(SNPs) selected from the group consisting of: rs10988087,
rs1573706, rs17575455, rs2487896, rs3135391, rs6097801 and
rs947603, and wherein step (ii) further comprises identifying the
subject as a predicted responder to glatiramer acetate if the
genotype of the subject contains one or more A alleles at the
location of rs10988087, one or more C alleles at the location of
rs17575455, or one or more G alleles at the location of
rs1573706, rs2487896, rs3135391, rs6097801 or rs947603.
3. The method of claim 1 or claim 2, wherein administering the
pharmaceutical composition comprising glatiramer acetate and a
pharmaceutically acceptable carrier comprises administering to
the human subject three subcutaneous injections of the
pharmaceutical composition over a period of seven days with at
least one day between every subcutaneous injection.
4. The method of any one of claims 1-3, wherein the pharmaceutical
composition is a unit dose of a 1 ml aqueous solution comprising
40 mg of glatiramer acetate.
5. The method of any one of claims 1-3, wherein the pharmaceutical
composition is a unit dose of a 1 ml aqueous solution comprising
20 mg of glatiramer acetate.
6. The method of any one of claims 1-3, wherein the pharmaceutical
composition is a unit dose of a 0.5 ml aqueous solution
comprising 20 mg of glatiramer acetate.
7. The method of any one of claims 1-5, wherein the pharmaceutical
composition comprising glatirarner acetate and a pharmaceutically
acceptable carrier is administered as a monotherapy.
8. The method of any one of claims 1-7, wherein the pharmaceutical
composition comprising glatirarner acetate and a pharmaceutically
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acceptable carrier is administered in combination with at least
one other multiple sclerosis drug.
9. A method of identifying a human subject afflicted with multiple
sclerosis or a single clinical attack consistent with multiple
sclerosis as a predicted responder or as a predicted nonresponder
to glatiramer acetate, the method comprising
determining the genotype of the subject at a location
corresponding to the location of one or more single nucleotide
polymorphisms (SNPs) selected from the group consisting of
kgpl0090631, kgpl009249, kgpl0152733, kgpl0224254, kgpl0305127,
kgpl0351364, kgpl0372946, kgpl0404633 1 kgpl0412303 1 kgpl0523170 1
kgpl054273, kgpl0558725, kgpl0564659, kgpl0591989, kgpl0594414.
kgpl0619195, kgpl0620244. kgpl0632945, kgpl0633631, kgpl0679353,10. The method of claim 9 1 further comprising determining a genotype
of the subject at a location corresponding to the location of
one or more single nucleotide polymorphisms (SNPs) selected from
the group consisting of: rsl0988087 1 rs1573706 1 rs17575455 1
rs24878961 rs3135391~ rs6097801 and rs947603 1 and
identifying the human subject as a predicted responder to
glatiramer acetate if the genotype of the subject contains one or
more A alleles at the location of rsl0988087 I one or more C
alleles at the location of rsl75754551 or one or more G alleles
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at the location of rs1573706, rs2487896, rs3135391, rs6097801 or
rs947603, or
identifying the human subject as a predicted non-responder to
glatirarner acetate if the genotype of the subject contains no A
alleles at the location of rs10988087, no C alleles at the
location of rs17575455, or no G alleles at the location of
rs1573706, rs2487896, rs3135391, rs6097801 or rs947603.
11. The method of any one of claims 1-10, wherein the genotype is
determined from a nucleic acid-containing sample that has been
obtained from the subject.
12. The method of any one of claims 1-11, wherein determining the
genotype comprises using a method selected from the group
consisting of restriction fragment length polymorphism (RFLP)
analysis, sequencing, single strand conformation polymorphism
analysis {SSCP), chemical cleavage of mismatch {CCM),
denaturing high performance liquid chromatography {DHPLC),
Polymerase Chain Reaction (PCR) and an array, or a combination
thereof.
13. The method of claim 12, wherein the genotype is determined
using at least one pair of PCR primers and at least one probe.
14. The method of claim 12, wherein the array is selected from the
group consisting of a gene chip, and a TaqMan Open Array.
15. The method of claim 14, wherein the gene chip is selected from .
the group consisting of a DNA array, a DNA microarray, a DNA
chip, and a whole genome genotyping array.
16. The method of claim 12, wherein the array is a TaqMan Open
Array.
17. The method of any of claims 14-15, wherein the gene chip is a
whole genome genotyping array.
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18. The method of any one of claims 1-17, wherein determining the
genotype of the subject at the location corresponding to the
location of the said one or more SNPs comprises:
(i) obtaining DNA from a sample that has been obtained from the
subject;
(ii) optionally amplifying the DNA; and
(iii) subjecting the DNA or the amplified DNA to a method selected
from the group consisting of restriction fragment length
polymorphism (RFLP) analysis, sequencing, single strand
conformation polymorphism analysis (SSCP), chemical cleavage
of mismatch (CCM), denaturing high performance liquid
chromatography (DHPLC), Polymerase Chain Reaction (PCR) and
an array, or a combination thereof, for determining the
identity the one or more SNPs.
19. The method of claim 18, wherein the array comprises a plurality
of probes suitable for determining the identity of the one or
more SNPs.
20. The method of any of claims 17-18, wherein the array is a gene
chip.
21. The method of claim 20, wherein the gene chip is a whole genome
genotyping array.
22. The method of any one of claims 1-21, wherein the human subject
is a naive patient.
23. The method of any of claims 1-21, wherein the human subject has
been previously administered glatiramer acetate.
24. The method of any of claims 1-21, wherein the human subject has
been previously administered a multiple sclerosis drug other
than glatiramer acetate.
25. The method of any one of claims 1-24, wherein the genotype is
determined at locations corresponding to the locations of 2, 3,
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4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or more single
nucleotide polymorphisms (SNPs) .
26. The method of any one of claims 1-24, wherein the one or more
SNPs is selected from the group consisting of kgp24415534,
kgp6214351, kgp6599438' kgp7747883' kgp8110667' kgp8817856,
rs10162089, rs16886004, rs1894408, rs3135391, and rs759458.
27. The method of claim 26, wherein the one or more SNPs comprise 2,
3, 4, 5, 6, 7, 8, 9 or 10 of the SNPs selected from the group
consisting of kgp24415534, kgp6214351, kgp6599438, kgp7747883,
kgp8110667, kgp8817856, rs10162089, rs16886004, rs1894408,
rs3135391, and rs759458.
28. The method of claim 26 or 27, wherein if rs3135391 is the one
SNP selected, then selecting at least one SNP other than
rs3135391.
29. The method of any one of claims 1-24, wherein the one or more
SNPs is selected from the group consisting of kgp24415534,
kgp6214351, kgp6599438, kgp8110667, kgp8817856, rs10162089,
rs16886004, rs1894408, rs3135391, and rs759458.
30. The method of claim 26, wherein the one or more SNPs comprise 2,
3, 4, 5, 6, 7, 8, 9 or 10 of the SNPs selected from the group
consisting of kgp24415534, kgp6214351, kgp6599438, kgp8110667,
kgp8817856, rs10162089, rs16886004, rs1894408, rs3135391, and
rs759458.
31. The method of claim 29 or 30, wherein if rs3135391 is the one
SNP selected, then selecting at least one SNP other than
rs3135391.
32. The method of any one of claims 1-31, wherein the genotype of
the subject at the location corresponding to the location of one
or more of the SNPs is determined indirectly by determining the
genotype of the subject at a location corresponding to the
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location of at least one SNP that is in linkage disequilibrium
with the one or more SNPs.
33. The method of any one of claims 1-31, wherein the genotype of
the subject at the location corresponding to the location of the
one or more SNPs is determined by indirect genotyping.
34. The method of claim 33, wherein the indirect genotyping allows
identification of the genotype of the subject at the location
corresponding to the location of the one or more SNPs with a
probability of at least 85%.
35. The method of claim 34, wherein the indirect genotyping allows
identification of the genotype of the subject at the location
corresponding to the location of the one or more SNPs with a
probability of at least 90%.
36. The method of claim 35, wherein the indirect genotyping allows
identification of the genotype of the subject at the location
corresponding to the location of the one or more SNPs with a
probability of at least 99%.
37. The method of any one of claims 1-36, further comprising the
step of determining the log number of relapses in the last two
years for the human subject.
38. The method of any one of claims 1-37, further comprising the
step of determining the baseline Expanded Disability Status
Scale {EDSS) score for the human subject.
39. The method of any one of claims 1-38, further comprising
applying the algorithm depicted in Figure 8 or in Figure 9 to
identify the subject as a predicted responder or as a predicted
non-responder to glatiramer acetate.
40. The method of any one of claims
determining the genotype of the
1-38, further comprising
subject at a location
corresponding to the location of one or more single nucleotide
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- 193 -
polymorphisms (SNPs) selected from the group consisting of: 43. A kit for identifying a human subject afflicted with multiple
sclerosis or a single clinical attack consistent with multiple
sclerosis as a predicted responder or as a predicted nonresponder
to glatiramer acetate, the kit comprising at least one
pair of PCR primers designed to amplify a DNA segment which
includes the location of a SNP selected from the group consisting
of kgpl0090631, kgpl009249, kgpl0152733, kgpl0224254,
kgpl0305127, kgpl0351364, kgpl0372946, kgpl0404633, kgpl0412303, 48. The kit of any of claims 42-47, further comprising instructions
for use of the kit for identifying a human subject afflicted with
multiple sclerosis or a single clinical attack consistent with
multiple sclerosis as a predicted responder or as a predicted
non-responder to glatiramer acetate.
49. The kit of any one of claims 42-48, wherein the one or more
single nucleotide polymorphisms (SNPs) are selected from the
group consisting of kgp24415534, kgp6214351, kgp6599438,
kgp7747883, kgp8110667, kgp8817856, rs10162089, rs16886004,
rs1894408, rs3135391, and rs759458.
50. The kit of claim 49, wherein the one or more single nucleotide
polymorphisms (SNPs) comprise 2, 3, 4, 5, 6, 7, 8, 9 or 10 of the
SNPs selected from the group consisting of kgp24415534,
kgp6214351, kgp6599438, kgp7747883, kgp8110667, kgp8817856,
rsl0162089, rs16886004, rsl894408, rs3135391, and rs759458.
51. The kit of claim 49 or 50, wherein if rs3135391 is the one SNP
selected, then selecting at least one SNP other than rs3135391.
52. The kit of claims 42-48, wherein the one or more SNPs is
selected from the group consisting of kgp24415534, kgp6214351,
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kgp6599438, kgp8110667' kgp8817856, rsl0162089, rs16886004,
rs1894408, rs3135391, and rs759458.
53. The kit of claim 52, wherein the one or more SNPs comprise 2, 3,
4, 5, 6, 7, 8, 9 or 10 of the SNPs selected from the group
consisting of kgp24415534, kgp6214351, kgp6599438, kgp8110667,
kgp8817856, rs10162089, rs16886004, rs1894408,. rs3135391, and
rs759458.
54. The method of claim 52 or 53, wherein if rs3135391 is the one
SNP selected, then selecting at least one SNP other than
rs3135391.
55. A kit for identifying a human subject afflicted with multiple
sclerosis or a single clinical attack consistent with multiple
sclerosis as a predicted responder or as a predicted nonresponder
to glatiramer acetate, the kit comprising
a) at least one probe specific for a location corresponding to
the location of at least one SNP;
b) at least one pair of PCR primers designed to amplify a DNA
segment which includes a location corresponding to the
location of at least one SNP;
c) at least one pair of PCR primers designed to amplify a DNA
segment which includes a location corresponding to the
location of at least one SNP and at least one probe specific
for a location corresponding to the location of at least one
SNP;
d) a reagent for performing a method selected from the group
consisting of restriction fragment length polymorphism (RFLP)
analysis, sequencing, single strand conformation polymorphism
analysis (SSCP), chemical cleavage of mismatch (CCM), gene
chip and denaturing high performance liquid chromatography
(DHPLC) for determining the identity of at least one SNP; or
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e) reagents for TaqMan Open Array assay designed for determining
the genotype at a location corresponding to the location of at
least one SNP, rs9817308,
rs9931211.
rs9834010,
- 219 -
rs9876830,
PCT/US2014/06164 7
rs9913349, rs9931167 and
56. The kit of claim 55, wherein the at least one single nucleotide
polymorphisms {SNPs) are selected from the group consisting of
kgp24415534, kgp6214351, kgp6599438, kgp7747883, kgp8110667,
kgp8817856, rsl0162089, rs16886004, rs1894408, rs3135391, and
rs759458,
preferably wherein the kit further comprises instructions for use
of the kit for identifying a human subject afflicted with
multiple sclerosis or a single clinical attack consistent with
multiple sclerosis as a predicted responder or as a predicted
non-responder to glatiramer acetate.
57. The kit of claim 55, wherein the at least one single nucleotide
polymorphisms {SNPs) comprise 2, 3, 4, 5, 6, 7, 8, 9 or 10 of the
SNPs selected from the group consisting of kgp24415534,
kgp6214351, kgp6599438, kgp7747883, kgp8110667, kgp8817856,
rs10162089, rsl6886004, rs1894408, rs3135391 and rs759458.
58. The kit of claim 56 or 57, wherein if rs3135391 is the at least
one SNP selected, then selecting at least one SNP other than
rs3135391.
59. The kit of claim 55, wherein the at least one single nucleotide
polymorphisms { SNPs) are selected from the group consisting of
kgp24415534, kgp6214351, kgp6599438, kgp8110667, kgp8817856,
rs10162089, rs16886004, rs1894408, rs3135391 and rs759458,
preferably wherein the kit further comprises instructions for use
of the kit for identifying a human subject afflicted with
multiple sclerosis or a single clinical attack consistent with
multiple sclerosis as a predicted responder or as a predicted
non-responder to glatiramer acetate.
60. The kit of claim 59, wherein the at least one single nucleotide
polymorphisms {SNPs) further comprise 2, 3, 4, 5, 6, 7, 8, or 9
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of the SNPs selected from the group consisting of kgp24415534,
kgp6214351, kgp6599438, kgp8110667, kgp8817856, rsl0162089,
rsl6886004, rsl894408, rs3135391 and rs759458.
61. The kit of any one of claims 42-60, wherein the genotype of the
subject at the location corresponding to the location of one or
more of the SNPs is determined by indirect genotyping.
62. The kit of any one of claims42-60, wherein the genotype of the
subject at the location corresponding to the location of one or
more of the SNPs is determined indirectly by determining the
genotype of the subject at a location corresponding to the
location of at least one SNP that is in linkage disequilibrium
with the one or more SNPs.
63. The kit of claim 55-62, comprising
a) at least one probe specific for a location corresponding to
the location of at least one SNP;
b) at least one pair of PCR primers designed to amplify a DNA
segment which includes a location corresponding to the
location of at least one SNP;
c) at least one pair of PCR primers designed to amplify a DNA
segment which includes a location corresponding to the
location of at least one SNP and at least one probe specific
for a location corresponding to the location of at least one
SNP;
d) a reagent for performing a method selected from the group
consisting of restriction fragment length polymorphism (RFLP)
analysis, sequencing, single strand conformation polymorphism
analysis ( SSCP) , chemical cleavage of mismatch (CCM) , gene
chip and denaturing high performance liquid chromatography
(DHPLC) for determining the identity of at least one SNP; or
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e) reagents for TaqMan Open Array assay designed for determining
the genotype at a location corresponding to the location of at
least one SNP,
wherein the at least one SNP is in linkage disequilibrium with
the one or more SNPs.
64. The kit of any one of claims 42-63, wherein determining the
genotype of the subject at a location corresponding to the
location of at least one SNP that is in linkage disequilibrium
with the one or more SNPs allows identification of the genotype
of the subject at the location corresponding to the location of
the one or more SNPs with a probability of at least 85%.
65. The kit of claim 64, wherein determining the genotype of the
subject at a location corresponding to the location of at least
one SNP that is in linkage disequilibrium with the one or more
SNPs allows identification of the genotype of the subject at the
location corresponding to the location of the one or more SNPs
with a probability of at least 90%.
66. The kit of claim 65, wherein determining the genotype of the
subject at a location corresponding to the location of at least
one SNP that is in linkage disequilibrium with the one or more
SNPs allows identification of the genotype of the subject at the
location corresponding to the location of the one or more SNPs
with a probability of at least 99%.
67.A probe for identifying the genotype of a location corresponding
to the location of a SNP selected from the group consisting of
kgp10090631, kgp1009249, kgp10148554, kgpl0152733, kgp10215554,
kgp10224254, kgp10305127. kgp10351364, kgpl0372946, kgp10404633,
kgpl0412303, kgp10523170, kgp1054273, kgp10558725, kgp10564659,
kgp10591989, kgp10594414, kgp10619195, kgpl0620244, kgp10632945,
kgp10633631, kgp10679353, kgp10762962, kgp10788130, kgp10826273,
kgp10836214' kgp10910719 1 kgp10922969 1 kgp10948564 1 kgp10967046,
kgp10974833, kgp1098237, kgp10989246, kgpl1002881, kgp11010680, 68. A probe for identifying the genotype of a location
corresponding to the location of a SNP selected from the group
consisting of kgp24415534, kgp6214351, kgp6599438, kgp7747883,
kgp8110667, kgp8817856, rsl0162089, rsl6886004, rs1894408,
rs3135391, and rs759458.
69. The probe of claim 68 wherein the location of a SNP selected
from the group consisting of kgp24415534, kgp6214351, kgp6599438,
kgp8110667. kgp8817856, rsl0162089, rs16886004, rsl894408,
rs3135391 and rs759458.
70. The probe of claim 67-69, wherein if rs3135391 is the one SNP
selected, then selecting a SNP other than rs3135391.
71. The probe of any one of claims 67-70, wherein the SNP is in
linkage disequilibrium with the one or more SNPs.
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72. The probe of any one of claims 67-701 wherein the location of
the SNP is determined indirectly by determining the genotype at a
location corresponding to the location of the SNP that is in
linkage disequilibrium with the one or more SNPs.
73. Glatiramer acetate or a pharmaceutical composition comprising
glatiramer acetate for use in treating a human subject afflicted
with multiple sclerosis or a single clinical attack consistent
with multiple sclerosis which human subject is identified as a
predicted responder to glatiramer acetate by:
a) determining a genotype of the subject at a location
corresponding to the location of one or more single nucleotide
polymorphisms (SNPs) selected from the group consisting of:
kgpl00906311 kgp10092491 kgp101527331 kgp102242541
kgp103051271
kgp104123031
kgp105646591
kgp106202441
kgp107881301
kgp109485641
kgp11002881 1
kgp11206453 1
kgpl12858621
kgp114534061
kgp115806951
kgpl03513641
kgp105231701
kgpl05919891
kgp106329451
kgp108262731
kgpl09670461
kgpl10106801
kgpl1210903 1
kgp113286291
kgpl1467007 1
kgpl16275301
kgpl0372946 1
kgp10542731
kgp105944141
kgpl06336311
kgpl09107191
kgp109748331
kgpl1077373 1
kgp11244921
kgp113563791
kgpl1514107 1
kgpl16339661
kgp104046331
kgp10558725 1
kgp106191951
kgp106793531
kgp109229691
kgp10982371
kgp11141512 1
kgp112815891
kgp114075601
kgp115439621
kgpl16861461
kgp117024741 kgp117115241 kgpll7685331 kgpl18048351
kgpll8431771 kgp120089551 kgp120839341 kgp121827451
kgp122303541 kgpl2244401 kgp123717571 kgp1241621 kgp124266241
kgp125573191 kgp12854411 kgpl31617601 kgp13559771 kgp13718811
kgp153905221 kgp16834481 kgp16887521 kgp16996281 kgp17534451
kgp17792541 kgpl7860791 kgp183797741 kgp184320551 kgp185252571
kgp19125311 kgp195687241 kgp201639791 kgp20232141 kgp20450741
kgp204789261 kgp20928171 kgp211719301 kgp22457751 kgp22621661
kgp227785661 kgp227932111 kgp228119181 kgp228230221
kgp22829381 kgp22996751 kgp232986741 kgp23563881 kgp236729371 b) identifying the subject as a predicted responder to glatiramer
acetate if the genotype of the subject contains
one or more A alleles at the location of kgpl0152733 74. The glatiramer acetate or a pharmaceutical composition
comprising glatiramer acetate for use of claim 73 wherein
determining a genotype of the subject at a location corresponding
to the location of one or more single nucleotide polymorphisms
(SNPs) selected from the
kgp6214351, kgp6599438,
group consisting of:
kgp7747883, kgp8110667'
kgp24415534,
kgp8817856,
rsl0162089, rsl6886004, rs1894408, rs3135391, and rs759458.
75. The glatiramer acetate or a pharmaceutical composition
comprising glatiramer acetate for use of claim 73 wherein
determining a genotype of the subject at a location corresponding
to the location of one or more single nucleotide polymorphisms
(SNPs) selected from the group consisting of: kgp24415534,
kgp621435L kgp6599438, kgp8110667' kgp8817856, rsl0162089,
rs16886004, rsl894408, rs3135391 and rs759458.
76. The glatiramer acetate or a pharmaceutical composition
comprising glatiramer acetate for use of claim 73-75, wherein if
rs3135391 is the one or more SNP selected, then selecting a SNP
other than rs3135391.
77. Glatiramer acetate for use according to claim 73-76, wherein the
genotype of the subject at the location corresponding to the
location of one or more of the SNPs is determined indirectly by
determining the genotype of the subject at a location
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corresponding to the location of at least one SNP that is in
linkage disequilibrium with the one or more SNPs.
78. Glatiramer acetate for use according to claim 73 -761 wherein
determining the genotype of the subject at a location
corresponding to the location of at least one SNP that is in
linkage disequilibrium with the one or more SNPs allows
identification of the genotype of the subject at the location
corresponding to the location of the one or more SNPs with a
probability of at least 85%, 90%1 or 99%.
79.A method of determining the genotype of a human subject
comprising identifying whether the genotype of a human subject
contains
one or more A alleles at the location of kgp10152733~ kgp279772, kgp3991733 or kgp7242489 is determined indirectly
by determining the genotype of the subject at a location
corresponding to the location of at least one SNP that is in
linkage disequilibrium with the one or more SNPs.
81. The method of claim 78 or 80, wherein identifying the genotype
of a human subject at the location of kgp24415534, kgp6214351,
kgp6599438, kgp7747883, kgp8110667, kgp8817856, rs10162089,
rsl6886004, rs1894408, rs3135391, or rs759458.
82. The method of claim 81,
human subject at the
kgp6599438, kgp8110667,
wherein identifying the genotype of a
location of kgp24415534, kgp6214351,
kgp8817856, rs10162089, rs16886004,
rs1894408, rs3135391 and rs759458.
83. The method of any one of claims 78-81, wherein if rs3135391 is
the SNP selected, then selecting a SNP other than rs3135391.
84. The method of any one of claims 78-83, wherein the SNP is in
linkage disequilibrium with the one or more SNPs.
85. The method of any one of claims 78-83, wherein the genotype of
the human subject is determined indirectly by determining the
genotype of the human subject at a location corresponding to the
location of the SNP that is in linkage disequilibrium with the
one or more SNPs.
86. A method of identifying a human subject afflicted with multiple
sclerosis or a single clinical attack consistent with multiple
sclerosis who is predicted to have a slower course of disease
progression, comprising the steps of:
(i) determining a genotype of the subject at a location
corresponding to the location of one or more single
nucleotide polymorphisms (SNPs) selected from the group
consisting of: kgp10148554, kgp10215554, kgp10762962, (ii) identifying the subject as predicted to have a slower course
of disease progression if the genotype of the subject
contains
one or more A alleles at the location of kgp10762962,
kgpl1285883, kgp11604017, kgp1211163' kgp12253568,
kgp12562255, kgp2176915, kgp24521552, kgp2877482, kgp2993366,
kgp3188, kgp3624014, kgp394638, kgp4037661, kgp433351, 87. The method of claim 86, wherein the genotype of the subject at
the location corresponding to the location of one or more of the
SNPs is determined indirectly by determining the genotype of the
subject at a location corresponding to the location of at least
one SNP that is in linkage disequilibrium with the one or more
SNPs. 88. A kit for identifying a human subject afflicted with multiple
sclerosis or a single clinical attack consistent with multiple
sclerosis who is predicted to have a slower course of disease
progression, the kit comprising
a) at least one probe specific for a location corresponding to
the location of at least one SNP;
b) at least one pair of PCR primers designed to amplify a DNA
segment which includes a location corresponding to the
location of at least one SNP;
c) at least one pair of PCR primers designed to amplify a DNA
segment which includes a location corresponding to the
location of at least one SNP and at least one probe specific
for a location corresponding to the location of at least one
SNP;
d) a reagent for performing a method selected from the group
consisting of restriction fragment length polymorphism (RFLP)
analysis, sequencing, single strand conformation polymorphism
analysis (SSCP), chemical cleavage of mismatch (CCM), gene
chip and denaturing high performance liquid chromatography
(DHPLC) for determining the identity of at least one SNP; or
e) reagents for TaqMan Open Array assay designed for determining
the genotype at a location corresponding to the location of at
least one SNP,
wherein the at least one SNP is selected from the group
consisting of kgp10148554, kgpl0215554, kgp10762962, kgp10836214,
kgpl0989246, kgp11285883, kgpll604017, kgp11755256, kgp1211163,
kgpl2253568, kgpl2562255, kgp1432800, kgp1682126, kgpl758575,
kgp2176915,
kgp2993366,
kgp3598966,
kgp413 71441
kgp4892427,
kgp22839559,
kgp3188,
kgp3624014,
kgp433351,
kgp4970670,
kgp24521552,
kgp3287349,
kgp3697615,
kgp4456934,
kgp4985243,
kgp2877482 1
kgp3420309,
kgp394638,
kgp4575797,
kgp5252824,
kgp2920925,
kgp3488270, 89. The kit of claims 42-66, or claim 88, further comprising
applying the algorithm depicted in Figure 8 or Figure 9 to
identify the subject as a predicted responder or as a predicted
non-responder to glatiramer acetate.