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Title:
METHODS AND COMPOSITIONS FOR USE IN THE TREATMENT OF HYPERLIPIDEMIA
Document Type and Number:
WIPO Patent Application WO/2000/061069
Kind Code:
A2
Abstract:
Methods of treating a host suffering from hyperlipidemia resulting from elevated levels of at least one of VLDL and triglycerides are provided. In the subject methods, an effective amount of agent that reduces the level of active apoE, e.g. apoE inhibitor or apoE expression inhibitor, is administered to the host. The subject methods find particular use in the treatment of hosts suffering from Type IV or Type IIb hyperlipidemia. Also provided are non-human transgenic animal models for hyperlipidemia, as well as methods for making and using the subject animal models, e.g. in therapeutic agent screening applications.

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Inventors:
HUANG YADONG
MAHLEY ROBERT W
TAYLOR JOHN M
Application Number:
PCT/US2000/009672
Publication Date:
October 19, 2000
Filing Date:
April 11, 2000
Export Citation:
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Assignee:
UNIV CALIFORNIA (US)
International Classes:
A01K67/00; A61K38/02; A01K67/033; A61K31/70; A61K39/395; A61K49/00; C07H21/02; C07H21/04; C07K1/00; C07K14/00; C07K16/00; C07K16/18; C07K17/00; A61K; (IPC1-7): A61K/
Foreign References:
US5965553A1999-10-12
US5770594A1998-06-23
Other References:
SAMPIETRO T. ET AL.: 'Behavior of Lp(a) and apoproteins (A1, B, C2, C3, E) during and after therapy with simvastatin' CARDIOVASCULAR DRUGS AND THERAPY, vol. 9, 1995, pages 785 - 789, XP002931877
SAITO M. ET AL.: 'Triglyceride-rich lipoproteins from apolipoprotein E3/2 subjects with hypertriglyceridemia enhance cholesteryl ester synthesis in human macrophages' ATHEROSCLEROSIS, vol. 129, 1997, pages 73 - 77, XP002931876
BRANCH A.D.: 'A good antisense molecule is hard to find' TIBS, vol. 23, February 1998, pages 45 - 50, XP002931875
Attorney, Agent or Firm:
Field, Bret E. (Field & Francis LLP Suite 200, 200 Middlefield Roa, Menlo Park CA, US)
Download PDF:
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Claims:
WHAT IS CLAIMED IS:
1. A method for reducing the plasma level of at least one of VLDL and triglycerides in a host, said method comprising: administering to said host an effective amount of an agent which at least reduces the amount of plasma active apoE in said host.
2. The method according to Claim 1, wherein said agent inhibits apoE.
3. The method according to Claim 1, wherein said agent reduces expression of apoE.
4. The method according to Claim 1, wherein said apoE is apoE3.
5. A method of treating a host suffering from a disease condition associated with elevated plasma levels of at least one of VLDL and triglycerides, said method comprising: administering to said host an effective amount of an agent that at least reduces the plasma amount of active apoE in said host.
6. The method according to Claim 5, wherein said disease condition is a hyperlipidemia.
7. The method according to Claim 6, wherein said hyperlipidemia is Type IV hyperlipidemia.
8. The method according to Claim 6, wherein said hyperlipidemia is Type IIb hyperlipidemia.
9. The method according to Claim 5, wherein said agent inhibits said apoE.
10. The method according to Claim 5, wherein said agent reduces expression of said apoE.
11. The method according to Claim 5, wherein said apoE is apoE3.
12. A nonhuman transgenic animal model of hyperlipidemia, wherein said nonhuman animal model overexpresses human apo E in a manner sufficient to have a high apoE plasma level, with the proviso that when said nonhuman transgenic animal model is a lagomorph, said apoE is apoE3.
13. The nonhuman transgenic animal model according to Claim 12, wherein said hyperlipidemia is selected from the group consisting of: (a) hypercholesterolemia; (b) hypertriglyceridemia; and (c) hypertriglyceridemia and hypercholesterolemia.
14. The nonhuman transgenic animal model according to Claim 13, wherein said hyperlipidemia is hypertriglyceridemia.
15. The nonhuman transgenic animal model according to Claim 14, wherein said hyperlipidemia is Type IV hyperlipidemia.
16. The nonhuman transgenic animal model according to Claim 13, wherein said hyperlipidemia is hypertriglyceridemia and hypercholesterolemia.
17. The nonhuman transgenic animal model according to Claim 16, wherein said hyperlipidemia is Type IIb hyperlipidemia.
18. The nonhuman transgenic animal model according to Claim 12, wherein said animal model does not express endogenous apolipoprotein E.
19. The nonhuman transgenic animal model according to Claim 18, wherein said animal is a mouse.
20. A rodent transgenic animal model of hypertriglyceridemia that overexpresses human apolipoprotein E and does not express endogenous apolipoprotein E.
21. The transgenic animal model according to Claim 20, wherein said rodent is a mouse.
22. The transgenic animal model according to Claim 21, wherein said mouse has plasma human apolipoprotein E levels in excess of about 25 mg/dl.
23. The transgenic animal model according to Claim 20, wherein said hypertriglyceridemia is Type IV hyperlipidemia.
24. A lagomorph transgenic animal model of hyperlipidemia that overexpresses human apolipoprotein E3.
25. The transgenic animal model according to Claim 24, wherein said animal is a rabbit.
26. The transgenic animal model according to Claim 24, wherein said hyperlipidemia is Type IIb hyperlipidemia.
27. The transgenic animal model according to Claim 24, wherein said rabbit has plasma human apolipoprotein E3 levels in excess of about 15 mg/dl.
28. A method for screening a compound to determine its effectiveness in treating a disease condition associated with elevated plasma levels of at least one of VLDL and triglycerides, said method comprising : administering a candidate compound to a nonhuman animal model according to Claim 12; and determining the effect of said candidate compound on said nonhuman animal model.
29. The method according to Claim 28, wherein said disease condition is hyperlipidemia.
30. The method according to Claim 29, wherein said hyperlipidemia is hypertriglyceridemia.
31. The method according to Claim 30, wherein said hyperlipidemia is Type IV hyperlipidemia.
32. The method according to Claim 29, wherein said hyperlipidemia is hypertriglyceridemia and hypercholesterolemia.
33. The method according to Claim 32, wherein said hyperlipidemia is Type IIb hyperlipidemia.
34. A therapeutic compound identified using the screening method of Claim 28.
35. A pharmaceutical composition of the therapeutic compound of Claim 34.
Description:
INTERNATIONALSEARCHREPORTInternationalapplicationNo. PCT/US00/09672 C(Continuation).DOCUMENTSCONSIDEREDTOBERELEVANT Category*Citationofdocument,withindication,whereappropriate, oftherelevantpassagesRelevanttoclaimNo. XUS5,770,594A(HAMANAKAetal.)23June1998,col.1,lines1,5,6 10-48,col.2,lines16-20,col.25,lines36-61 Y2-4,7-11 ABRANCHA.D.AGoodAntisenseMoleculeisHardtoFind.2,3,9,10 TIBS.February1998.Vol.23.pages45-50,seeentirearticle. INTERNATIONALSEARCHREPORTInternationalapplicationNu. PCT/USOO/09672 BoxIObservationswherecertainclaimswerefoundunsearchable(Cont inuationofitemIoffirstsheet) Thisinternationalreporthasnotbeenestablishedinrespectofcerta inclaimsunderArticle17(2)(a)forthefollowingreasons: 1.FClaimsNos.: becausetheyrelatetosubjectmatternotrequiredtobesearchedbythi sAuthority,namely: 2. 2 Claims Nos.: becausetheyrelatetopartsoftheinternationalapplicationthatdon otcomplywiththeprescribedrequirementstosuch anextentthatnomeaningfulinternationalsearchcanbecarriedout,s pecifically: 3.2 ClaimsNos.: becausetheyaredependentclaimsandarenotdraftedinaccordancewit hthesecondandthirdsentencesofRule6.4(a). BoxIIObservationswhereunityofinventionislacking(Continuation ofitem2offirstsheet) ThisInternationalSearchingAuthorityfoundmultipleinventionsin thisinternationalapplication,asfollows: PleaseSeeExtraSheet. 1. fezAsallrequiredadditionalsearchfeesweretimelypaidbytheappli cant,thisinternationalsearchreport covers allsearchable u claims. 2.FAsallsearchableclaimscouldbesearchedwithouteffortjustifyi nganadditionalfee,thisAuthoritydidnotinvitepayment ofanyadditionalfee. 3.j) As on) ysomeoftherequiredadditionalsearchfeesweretimelypaidbytheapp licant.thisinternationalsearchreportcovers onlythoseclaimsforwhichfeeswerepaid,specificallyclaimsNos.: 4.FNôrequiredadditionalsearchfeespaidtimelypaidbysearchappl icant.Consequently, restrictedtotheinventionfirstmentionedintheclaims;itiscovere dbyclaimsNos.: 1-11 RemarkonProtestTheadditionalsearchfeeswereaccompaniedbytheap plicant'sprotest. Noprotestaccompaniedthepaymentofadditionalsearchfees. INTERNATIONALSEARCHREPORTInternationalapplicationNo. PCT/US00/09672 B. FIELDS SEARCHED Electronic data bases consulted (Name of data base and where practicable terms used): WEST, MEDLINE, EMBASE BIOSIS, INPADOC, CAPLUS, ADONIS search terms: apoE, apoE3, apolipoprotein, hyperlipidemia, antisense, ribozyme, atorvastatin. simvastatin, inhibition, reduction, plasma, type IIb hyperlipidemia, type IV hyperiipidemia, antibody, antibodies, agents. drugs, inhibitors.

BOX II. OBSERVATIONS WHERE UNITY OF INVENTION WAS LACKING This ISA found multiple inventions as follows: This application contains the following inventions or groups of inventions which are not so linked as to form a single inventive concept under PCT Rule 13.1. In order for all inventions to be searched, the appropriate additional search fees must be paid.

Group I, claim (s) I-11, drawn to methods for reducing the plasma level of at least one of VLDL and triglycerides in a host, and for treating a host suffereing from a disease condition associated with elevated plasma levels of at least one of VLDL and triglycerides.

Group II, claim (s) 12-19 and 28-35, drawn to a non-human transgenic animal model of hyperlipidemia, a method for screening a compound using the non-human transgenic animal model of hyperlipidemia, and a therapeutic/pharmaceutical compound identified by the screening method.

Group III, claim (s) 20-23, drawn to a rodent transgenic animal model of hypertriglyceridemia that over-expresses human apolipoprotein E and does not express endogenous apolipoprotein E.

Group IV, claims 24-27, drawn to a lagomorph transgenic animal model of hyperlipidemia that over-expresses human apolipoprotein E3.

The inventions listed as Groups I-IV do not relate to a single inventive concept under PCT Rule 13.1 because. under PCT Rule 13.2, they lack the same or corresponding special technical features for the following reasons: the methods of Groups I and II are distinct one from the other because the method of Group II requires different reagents, different technical considerations, and requires different protocols, e. g., the method of Group II requires a transgenic animal and the method of making the transgenic animal is not required in the methods of Group I, directed to reducing the plasma level of at least one of VLDL and triglycerides in a host, and treating a host suffering from elevated plasma levels of VLDL or triglycerides. In addition, the methods of Group I do not require the transgenic animals of Groups III or IV, thus there is no corresponding special technical feature between the methods of Group I and the transgenic animals of Groups II-IV. Groups II, III, and IV lack the same or corresponding special technical feature because the transgenic animals of Groups II, III, and IV require different phenotypes, thus making the transgenic animals of Groups Il-IV requires different technical considerations, different polynucleotide constructs for generating the transgenic animas, and results in different products.




 
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