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(12) Patent Application Publication (10) Pub. No.: US 2003/0198970 A1 Roberts (43) Pub US 2003O19897OA1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0198970 A1 Roberts (43) Pub. Date: Oct. 23, 2003 (54) GENOSTICS clinical trials on groups or cohorts of patients. This group data is used to derive a Standardised method of treatment (75) Inventor: Gareth Wyn Roberts, Cambs (GB) which is Subsequently applied on an individual basis. There is considerable evidence that a significant factor underlying Correspondence Address: the individual variability in response to disease, therapy and FINNEGAN, HENDERSON, FARABOW, prognosis lies in a person's genetic make-up. There have GARRETT & DUNNER been numerous examples relating that polymorphisms LLP within a given gene can alter the functionality of the protein 1300 ISTREET, NW encoded by that gene thus leading to a variable physiological WASHINGTON, DC 20005 (US) response. In order to bring about the integration of genomics into medical practice and enable design and building of a (73) Assignee: GENOSTIC PHARMA LIMITED technology platform which will enable the everyday practice (21) Appl. No.: 10/206,568 of molecular medicine a way must be invented for the DNA Sequence data to be aligned with the identification of genes (22) Filed: Jul. 29, 2002 central to the induction, development, progression and out come of disease or physiological States of interest. Accord Related U.S. Application Data ing to the invention, the number of genes and their configu rations (mutations and polymorphisms) needed to be (63) Continuation of application No. 09/325,123, filed on identified in order to provide critical clinical information Jun. 3, 1999, now abandoned. concerning individual prognosis is considerably less than the 100,000 thought to comprise the human genome. The iden (30) Foreign Application Priority Data tification of the identity of the core group of genes enables the invention of a design for genetic profiling technologies Jun. 6, 1998 (GB)......................................... 98.120983 which comprises of the identification of the core group of Dec. 23, 1998 (GB)......................................... 98.28289.0 genes and their Sequence variants required to provide a broad base of clinical prognostic information-genostics. Publication Classification The “GenosticTM' profiling of patients and persons will radically enhance the ability of clinicians, healthcare pro (51) Int. Cl." ............................. C12Q 1/68; CO7H 21/04 fessionals and other parties to plan and manage healthcare (52) U.S. Cl. ............................................... 435/6; 536/24.3 provision and the targeting of appropriate healthcare resources to those deemed most in need. The use of our (57) ABSTRACT invention could also lead to a host of new applications for People vary enormously in their response to disease and the Such profiling technologies, Such as identification of perSons also in their response to therapeutic interventions aimed at with particular work or environment related risk, Selection of ameliorating the disease proceSS and progression. However, applicants for employment, training or Specific opportunities the provision of medical care and medical management is or for the enhancing the planning and organisation of health centered around observations and protocols developed in Services, education Services and Social Services. Patent Application Publication Oct. 23, 2003 Sheet 1 of 2 US 2003/0198970 A1 SCHIZOPHRENA Eleg coREENERPERoostectSTANDARD ORALNEUROLEPTIC E CONNEWHORA,THERAPYOR NOTCHOICE COLLABORATEIN OF TREATMENT THEIR ATSTANDARDDOSES onRATED CANSESEISREADHERENCETOTHERAPY ASSESS OVERATLEAST4 WEEKS NEFFECTIVE NOT TOLERATED CHANGETODIFFERENT CLASS OFORAL ASSESSEFFICIENCY AND NEUROLEPTICATSTANDARDDOSES TOLERANCERECONSEDRATINGSCALES. WITH TRY"FFSDROFORY6ERATE" ATYPICAL"DRUGORSULPRIDEF EFFECTIVE.CONTINEWCASEAFOR RSisSERSEANSSESSTRYAVE FNEGATIVESYMPTOMSPREDOMINATE FESEARESEVEREOROERED CHANGE9E9E9ESSREADHERENCETOTHERAPY AVOIDNEUROLEPTIC, ASSESS OVERATLEAST4 WEEKS POLYPHARMACY -ORAL +DEPOTARE INEFFECTIVE NOT TOLERATED RARELYNECESSARY CONSIDERAUGMENTING WITH THIUM SEREOF (EEEEEEEOINE SYSSYNE SHORTCONAZEPAMIFSEDATION TERM AGRESSIONORASAMOODSSESS ES STABILISER) TOLERATEDEFFECTIVE REGULARLYWITH BENZODIAZEPINES LONGERMTHERAPY NOT ISREQUIRED RECOMMENDED |NACUTEPSYCHOSIS ASSESS OVERATLEAST4 WEEKS INEFFECTIVE NOT TOERATED CONSORENDOEO EFF IFMEASURED IMPROVEMENT, EASNEUROLEPTICS. DO NOT COLLEGEDELINESFOLLOWEDAEGEE FROYAL EFFECTIVE DOCUMENTINNOTES AND EXCEED RECOMMENDED TPRECG, etc (SEE BNF) TOLERATED CONTINUE WITHDEPOT y REVIEWFREQUENTLY DOSEFORAYPCADRUGS ASSESSOVERALEAST4WEEKSBUTNOLONGER THAN3 MONTHS INEFFECTIVE NOT TOLERATED SOMESUPPORT FORTHE USE CHANCETOCOZAPNE OFCOZAPINESEAFORA R GIVEDGSE OFrom DALY TOERATEDEFFECTIVE CONTINUEATREDUCEDDOSEEMEASUREDIMPROVEMENT 350mcg PERLITRE ASSESS OVERATLEAST6 MONTHS NEFFECTIVE NOT TOLERATED PERFORMCOMPLETEDRUGHISTORY REVIEWDAGNOSIS CONSIDER WITHDRAWING ALL (NEYESEFFECTIVEDRUG PREVIOUSLY AND GIVE MOST PRESCRIBEDAT LOWEST DOSE FIG. 1 Patent Application Publication Oct. 23, 2003 Sheet 2 of 2 US 2003/0198970 A1 DEPRESSION DEPRESSION HISTORY OF DEPRESSIVE LLNESS2 ANTIDEPRESSANT EFFECTIVE IN THE PAST? NO YES ANY MEDICAL YES SEDATION YES CARDAC PROBLEMS CONTRAINDICATIONS DESRED? EPLEPSY? NO NO YES USEAGAINFOR SAME DRUG TRY NON-SEDATING TRY SEDATIVE APPROPRIATE TRICYCLICS (SUCH AS TRICYCLIC DURATION IMIPRAMINE) OR SSRIs SUCH AS (SUCH AS FLUOXETINE) AMITRIPTYLINE AVOD TRICYCLICS AS FARAS FAILED TO RESPOND POSSIBLE PREFERABLY TO ONEDRUG - USE SSRIS + SHORT COURSE OF BENZODIAZEPINE HASEPAENT TRY 6-8 WEEKSAT DRUG FOR 6 WEEKS2 OPTIMALDOSE (SUCH ASTRICYCLICS 150 mg/day) WASPATIENT GIVEN OPTIMUM DOSE YES "RASEFESSINT NO RESPONSE SEEKSPECIALIST CLASS AFTER 4WEEKS ADVICE FIG 2 US 2003/O19897O A1 Oct. 23, 2003 GENOSTICS factors will also influence the course of events (e.g. inter 0001 People vary enormously in their response to dis action of ApoE genotype and head injury in Alzheimer's ease and the also in their response to therapeutic interven disease Nicholl et al 1996). tions aimed at ameliorating the disease proceSS and progres 0008. The identification of modifier genes that influence Sion. However, the provision of medical care and medical the penetrance and expressivity of these risk alleles will be management is centered around observations and protocols key variables in assessing individual risk profiles. It is likely developed in clinical trials on groups or cohorts of patients. that the combination of and interaction between Small dis This group data is used to derive a Standardised method of crete genetic influences on a disease State represent the treatment which is Subsequently applied on an individual Single largest explanation for the phenotypic variation Seen basis (e.g. the comment that drugs are often prescribed on in medicine. the basis that everyone is a 70 kg white male). 0009. This opens the possibility that the identification of 0002. It is standard practice for clinicians to prescribe the the genes associated with disease and an understanding of Same Starting dose of a particular drug for a given indication how these genes interact with the environment, can lead to and then adjust the treatment regimen by monitoring the better prediction of the outcome of both the disease and the progreSS of the disease and therapeutic response in indi therapeutic process. This in turn would allow the tailoring of vidual patients. Observation of actual therapeutic outcome resources and therapy to meet the likely requirements of the following these adjustments to patient's therapy provides the individual patient (Marshall 1997a). The net result should be basis for determining a prognosis for the disease and devel improved clinical management, identification of the poten oping a clinical management plan for patient care (e.g. See tial for prevention, the reduction of the burden of disability FIG. 1, algorithm for management of Schizophrenia, from and, ultimately, improved quality of life for the individual FIG. 1 Taylor and Kerwin 1997, FIG. 2 algorithm for (Poste 1998). treatment of depression from FIG. 1 Pathare and Paton 0010. As a result of the appreciation of the contribution 1997) and treatment algorithms published by the National of genetic variation to medicine, considerable effort has been Cancer Institute). made to determine how individual genetic variations affect 0003. The standard practice of clinical management has overall health (including predisposition to disease) and once its disadvantages. In particular it is retro-active in that disease is manifest, the likely patterns of progression, changes to patient management will occur following the responsiveness to treatment and overall prognosis. emergence of therapeutic failures, adverse events or other 0011. In a quest to understand and plot the limits of difficulties in undertaking the therapeutic regime (Lazarou et genetic variation in humans the Human Genome Project was al 1998). launched in 1990 with a mission to sequence the code of all 0004. There is considerable evidence that a significant 100,000 or so human genes by 2002. factor underlying this individual variability in response to 0012. As a result of the Human Genome project not only disease, therapy and prognosis lies in a perSon's genetic is the mapping and Sequencing of the human genome make-up. There have been numerous examples relating that becoming well understood but also the degree of variability polymorphisms within a given gene can alter the function in gene Sequence between individuals
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