I
`I
`
`· . .;
`.
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(1") World 1n,':'o!"'=. o...,.u .. oon •
`
`/llllHllHDDllJllmlllJllllllWUlllf ODlmlliillllllOP
`
`(43) International Publication Date
`15 June 2006 (15.06.2006)
`
`(51) InternatlonaJ Patent Cl85.9lfk:atlon:
`A61K 48100 (2006.01)
`A61K 31116 (2006.01)
`A61K 31156 (2006.01)
`
`PCT
`
`(10) International Publication Number
`W 0 2006/063128 A2
`(74) Agents: HOSTE1LER, Michael, J. et al.; Wilson Sonsini
`Goodrich & Rosati, 650 Page Mill Road, Palo Alto, Cali(cid:173)
`fornia 94304-1050 (US).
`
`(21) InternaUonaJ Application Number:
`PCT/US200SI044416
`
`(22) lnternatlonaJ FUlng Date:
`7 December 2005 (07.12.2005)
`
`(25) FIUng Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(81) Designated States (unless otht!rwise indicaud. for t!Very
`kind of national protection availabk): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY. BZ, CA, CH, CN,
`CO, CR. CU, CZ, DE, DK, DM, DZ, EC, EE, EO, ES, Fl.
`GB, GD, GE, GH, GM, HR. HU, ID, ll., .JN, IS, JP, KE,
`· KG, KM, KN, KP, KR, KZ, LC, LK, LR, ~,'-LT, LU, LV,
`LY.MA, MD, MG, MK. MN, MW, MX, Mz. NA, NG, NI,
`NO, NZ, OM, PG, PH, PL, PT, RO; RU, SC, SD, SE, SG,
`·SK. SL, SM, SY. TJ, TM, TN, TR, TI, TZ, UA, UG, US,
`UZ, VC, VN, YU, ZA, ZM, ZW.
`.
`
`(84) Designated States (unless otherwise indicaJed. for every
`kind oi regional proteclion availabk): ARIPO (BW, GH,
`GM, KE, LS, MW, Mz. NA, SD, SL, SZ, TZ, UG, ZM,
`'ZW), Eurasian (AM, A'Z., BY, KG, KZ, MD, RU, TJ,-TM),
`European (AT, BE, BG, CH, CY. CZ, DB, DK, EB, BS, Fl,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT,
`RO, SE, SI, SK. TR), OAPI (BF, BJ, CF; CG, CI, CM, GA,
`GN, GQ, ow; ML, MR, NE; SN, To, TO).:.
`
`Published:
`-
`'without imemiJtional searrh 'report arid_ to be republished
`·
`upon receipt of that report
`
`For two-leller codes and otht!r abbreviaJwns, refer lo the •Guid(cid:173)
`ance Notes on Codes and Abbreviations• appearing al the begin(cid:173)
`ning of each regular .issue of the PCT G~tte.
`
`(JO) Priority Data:
`60/634,449
`60/660,924
`60/660,904
`60/672,405
`60/698,512
`
`8 December 2004 (08.12.2004)
`IO March 200S (10.03.2005)
`11 March 2005 (11.03.2005)
`18 April 2005 (18.04.2005)
`11July2005(l1.07.2005)
`
`us
`us
`us
`us
`us
`
`(71) Applicant (for all designaud Staus except US):
`SYTERA, INC. [US/US]; SOS Coast Blvd., South,
`Suite 412, La Jolla, California 92037 (US).
`
`_
`
`-
`-
`
`----
`= (72) Inventors; and
`-
`=
`=
`
`(75) Inventors/Applicants (for US only): WIDDER, Kenneth
`[US/US]; P.O. Box 676250, Rancho Santa Fe, California
`92067 (US). LICHTER, Jay [US/US]; 4950 Sandshore
`Ct., San Diego, California 92130 (US).
`
`= -------. -· --------
`
`QO
`N
`.....c
`~-~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
`~ (54) Title:. METHODS, ASSAYS AND COMPOSITIONS FOR TREATING RETINOL-RELATHD DISEASES
`...._
`\C
`Q
`(57) Abstract: Described herein are methods and compositions for treating certain retinol-related diseases and conditions by modu-
`Q
`lation of cranslhyretin (TfR) and retinal binding protein (RBP) availability in the subject. For example, the methods and compositions
`M provide for therapeutic agents for the treatment and/or prevention of age-related macular degeneration and/or dystrophies, metabolic
`O disorders, idiopathic intracranial hypenension, hyperostosis, and protein misfolding and aggregation diseases.' The comj,ositions
`::;;a... disclosed may be used as single agent therapy or in combination with other agents or thenipies. In addition, described herein are
`~ methods and assays for selecting appropriate agents that can modulate the TTR and RBP availability in a subject.
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`METHODS, ASSAYS AND COMPosmoNS FOR TREATING RETINOL-RELATED
`DISEASES
`
`RELATED APPUCATIONS
`
`[OOOlJ
`
`This patent application claims the benefit of (a) U.S. Provisional Application Ser. No ..
`
`5
`
`60/634,449, filed December 8, 2004, (b) U.S. Provisional Application Ser. No. 60/660,924~ filed March
`
`10, 2005, (c) U.S. Provisional Application serial number 60/660,904, filed on March 11~ 2005,·(d) U.S.
`
`Provisional Application serial number 60/672,405, filed on April 18, 2005, and (e) U.S. Provisional
`
`Application serial number 60/698,512, filed on July 11, 2005; the aforementioned pat.eat applications are
`
`herein incorporated by reference in their entirety.
`
`10
`
`15
`
`FIELD OF THE INVENTION
`
`[0002)
`The methods and compositions described herein are directed to the treatment ofretinol-
`related diseases in a subject by modulating the activity or availability of retinol binding protein (RBP) and
`transthyretin (1TR) in the subject.
`
`[0003}
`
`BACKGROUND OF Tiii; INVENTION
`Retinoids are essential for maintenance of nonnal groWth, development, immunity, .
`reproduction, vision and other physiological processes. Conversely, abnormal production or processing of
`retinoids correlates with the manifestation of disease proce8ses.
`
`[00041
`
`For example, more than I 00 milJion of the worJd's children are vitamin-A deficient, causing
`
`blindness and death among these children. Excess vitamin-A levels in target organs and tissues, such as
`
`20
`
`the eye, may also cause blindness in a variety of retinal diseases, including macular degeneration. A large .
`variety of conditions, generally referred to as vitreoretinal diseases, can affect the vitreous and retina that
`lie on the back part of the eye, including the retinopatbies and macular degenerations and dystropbies.
`
`Macular degeneration is a group of eye diseases that is the leading cause of blindness for those aged 55
`and older in the United States, affecting more than 10 million Americans. Some studies predict a six-fold
`
`25
`
`increase in the number of new cases of macular degeneration over the next decade, taking on the
`
`characteristics of an epidemic. Age-related macular degeneration or dystrophy, a particulady debilitating
`
`disease, leads to gradual loss of vision and eventually severe damage to the central vision.
`
`Abnormal levels of vitamin A, and/or its as8ociated transport proteins (retinol binding protein
`[0005)
`(RBP) and transthyretin {'ITR)) are also correlated with the manifestation of other diseases, including
`30 metabolic disorders. An example is seen in diabetes, where abnormal levels of retinol were seen in both
`type I and type Il diabetic patients, but not normal patients. Other diseases include pseudotumor cerebri
`(PTC), idiopathic intracranial hypertension (IIH), and bone-related disorders, including cervical
`spondylosis, spinal hyperostosis, and diffuse idiopathic skeletal hyperostosis (DISH). In addition, vitamin
`A and/or its associated transport proteins, 1TR in particular, may play a role in protein misfoldmg ~d
`aggregation diseases, including Alzheimer's disease and systemic amyloidosis.
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`[0006]
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`PCT/USZOOS/044416.
`Disorders associated with retinoid-related physiological manifestations continue to be a
`
`problem throughout the world. Therefore, there is a need to provide for methods and compositions to treat
`
`these diseases.
`
`SUMMARY OF THE INVENTION
`
`5
`
`[0007]
`Described herein are methods and compositions for identifying and detecting agents which
`modulate retinol binding protein (RBP) or transthyreti.n (ITR) levels or activity in a mammal. Also
`
`10
`
`15
`
`descn'bed herein are assays for identifying compounds and therapeutic agents, as well as methods and
`compositions for treating a subject or patient with reti.nol-related diseases by administration: of
`compounds or therapeutics agents, wherein said administration results in the modulati~ ofRBP or TIR,
`levels or activity in sai~ patient or subject Also descnl>ed herein are methods and compositions for .
`
`treating a patient with retinol-related c;liseases by modulating RBP or 1TR levels or activity in the patient·
`
`by administration of such compounds.
`
`Jn one embodiment, the methods and compositions disclosed herein provide for the
`[0008]
`modulation of RBP or 1TR levels or activity in a mammal comprising administering to the mammal at
`
`least once an effective amount of an agent which modulates RBP or TI'R. transcription in said mammal,
`wherein said modulati0n of RBP or TTR levels or activity reduces the formation of all-trans retinal in an
`eye of a mammal Jn one embodiment, the agent is chosen from the group consisting ofRXR/RAR •
`.
`.
`.
`.
`agonists, RXR/RAR antagonists, estrogen agonists, estrogen antagonists, testosterone agonisis,
`
`testosterone antagonists, progesterone agonists, progesterone antagonists, dexamethasone agonists,
`
`20 ·
`
`dexamethasone antagonists, anti.sense oligonucleotides, siRNA, fatty acid binding protein antagonists,
`
`C/EBP agonists, C/EBP antagonists, HNF-1 agonists, HNF-1 antagonists, HNF-3 agonists, HNF-3
`. .
`.
`antagonists, HNF-4 agonists, HNF-4 antagonists, HNF-6 agonists, HNF-6 antagonists, aptamers, Zn-
`
`.
`
`finger binding proteins, ribozymes and monoclonal antibodies.
`
`In yet another embodiment, the methods and compositions disclosed herein provide for.
`[0099]
`25 modulating RBP or 1TR levels or activity in a mammal comprising administering to the ~ammal at least
`
`once an effective amollllt of an RBP or TIR translation inhibitor, wherein said modulation ofRBP or
`TI'R levels or activity reduces the formation of all:..trans retinal in an eye of a mammal. The agent may be
`
`chosen from the group consisting of: RXRIRAR agonists, RXRIRAR antagonists, estrogen agonists,
`
`estrogen antagonists, testosterone agonists, testosterone antagonists, progesterone agonists, progesterone
`
`30
`
`antagonists, dexamethasone agonists, dexamethasone antagonists, anti.sense oligonucleoti?es, s~A,
`
`fatty acid binding protein antagonists, C/EBP agonists, C/EBP antagonists, HNF-1 agonists, HNF-: 1
`.. ·
`.
`.
`antagonists, HNF-3 agonists, HNF-3 antagonists, HNF-4 agonists, HNF-4 antagonists, HNF-6. agonists,
`
`HNF-6 antagonists, aptamers, nbozymes and monoclonal antibodies.
`
`35
`
`In one embodiment, the methods and compositions disclosed herein provide for modulating
`[0010]
`RBP or TI'R levels .or activity in a mammal comprising administering to the mammal at least once an
`effective amount of 8n agent which modulates RBP binding to 1TR in said mammal, wherein ·said
`modulation of RBP or 1TR levels or activity reduces the formation of all-trans retinal ~ an eye of a
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`·mammal. The modulating agent cim bind to RBP or TrR. so as to inluoit the binding of RBP to TI'R in ·
`the maIDJDal. The modulating agent can also antagonize the binding of retinol to RBP so as to inlnDit the
`binding of RBP or the RBP-agent complex to TI'R.. The modulating agent may be chosen from the:.grou; •
`
`consisting of: a retinyl derivative, a polyhalogenated aromatic hydrocarbon, a thyroid hormone agQnist, a ·
`
`5
`
`thyroid hormone antagonist, diclofenac, a diclofenac analogue, a small molecule compo\lnd, an endocrine
`
`hormone analogue, a flavonoid, a non-steroidal anti-inflammatory drug, a bivalent inln'bitor, a cardiac
`
`agent, a peptidomimetic, an aptamer, and an antibody.
`
`In one embodiment, the retinyl derivative of the methods and compositions disclosed herein ·
`[0011}
`is a compound having the structure:
`
`10
`
`15
`
`20
`
`25
`
`30
`
`(I),
`whereinX1 is selected from the group consisting ofNR2, 0, S, CHR2; R1 is (CHR2)x-L1':'R3, wherein xis
`0, 1, 2, or 3; Lt is a single bond or-C(O)-; R 2 is a moiety selected from the group consisting ofH, (Ct-
`
`4)alkyl, F, (C1-C4)fluoroalkyl, (C1-C4)alkoxy, -C(O)OH, -C(O)-NH2. -(Ct-C4)alkylamine; -C(O)-(Ci(cid:173)
`C4)alkyl, -C(O)-(C1-C4)fluoralkyl, -C(O)-(C1-4)alkylamine, and-C(O)-(Ct-C4)aJkoxy;·and R3 is Hor a
`moiety, optionally substituted with 1-3 independently selected substituents, selected from the group
`
`consisting of (Cz-C,)alkenyl, (Cz-C,)alkynyl, aryl, (C,-C7)cycloalkyl, (C5-C,)cycloalkenyl, =and a
`heterocycle; or an active metabolite, or a pharmaceutically acceptable prodrug or solvate thereof.
`[0012]
`
`In one embodiment, the retinyl derivative of the methods and compositions disclosed herein
`
`is a compo1Dld having the structure:
`
`x1.
`!1
`(II);
`whereinX1 is selected from the group consisting ofNR.2
`, 0, S, CHR2; R 1 is (CHR2h-L1-R3
`, wherein xis
`0, 1, 2, or 3; L 1 is a single bond or-C(O)-; R2 is a moiety selected from the group consisting of H, (C1-
`C4)alkyl, F, (C1-C4)fluoroalkyl, (C1-C4)alkoxy, -C(O)OH, -C(O)-NH2, -(C1-C4)alkylamine, -C(O)-(C1-
`C4)aJkyl, -C(O)-(Ci-C4)fluoroa1kyl, -C(O)-(C1-4)alkylamine, and-C(O)-(C1-C4)a1koxy; and R3 is Hor a
`moiety, optionally substituted with 1 ~3 independently selected substituents, select~d fro~ the group
`consisting of (~-C7)alkenyl, (Cz-C,)alkynyl, aryl, (C3-C1)cycloalkyl, (C.s~)cycloalkenyl~ anq a
`heterocycle; or an active metabolite, or a pharmaceutically acceptable prodrug or solvate thereof. ·
`In further embodiments (a) X 1 is NR2, wherein R2 is Hor (C1-C4)alkyl; (b) xis O; Cc) ,i. is 1
`[0013]
`and Lt is -C(O)-; (d) R3 is an optionally substituted aryl; (e) R3 is an optionally substinited het~oaryl; (f)
`xt is NH and R3 is an optionally substituted aryl, including yet further embodiments in ~hlch (i) the aryl
`group has one substituent, (ii) the aryl group has one substituent selected from the.group consisting of
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`halogen, OH, O(C1-C4)alkyl, NH(C1-C4)alkyl, O(C1-C4)fluoroalkyl, and N[(C1-CJalkyl]2, (iii) the aryl
`group has one substituent, which is OH, (v) die aryl is a phenyl, or (vi) the aryl is naphthyl; (g) the :
`
`~"' .
`
`¢NH
`
`. .
`.
`. • •
`
`.
`
`-
`
`.
`
`.
`
`compound is
`
`.
`oH , or an active metabolite, or a p~cally .
`acceptable prodrug or solvate thereof; (h) the compotmd is 4-hydroxyphenylretinamide, or a metabolite, ..
`or a pharmaceutically acceptable prodrug or solvate thereof; (i) the compound is 4-
`methoxyphenylretinamide, or G) 4-0xo fenretinide, or a metabolite, or a pbarmaceuticaliy acceptable
`
`5
`
`prod.rug or solvate thereof.
`In further embodiments, the administration of a compound of Formula (II) is used to treat
`(0014]
`ophthalmic conditions by lowering the levels of serum retinol in the body of a patient. In further
`
`10
`
`embodiments (a) the effective amount of the compound is systemically administered to the mammal; (b)
`
`15
`
`the effective amount of the compound is administered orally to the mammal; (c) the effective amount of
`the compound is intravenously administered to the mammal; (d) the effective amount·o~the compound is
`ophthalmically administered to the manunal; ( e) the effective amount of the compound is administered by
`iontophoresis; or (f) the effective amount of the compotmd is administered by injection to the mammal.
`(0015]
`In further embodiments the mammal is a huinan, including embodiments wherein (a) the
`human is a canier of the mutant ABCA4 gene for Stargardt Disease or the human bas a mutant ELOV4
`gene for Stargardt Disease, or has a genetic Variation in complement factor H associated with age-related
`
`macular degeneration, or (b) the human bas an ophthalmic condition or trait selected fro~ the group
`consisting of Stargardt Disease, recessive retinitis pigmentosa, geographic atrophy (of which scotoma is
`
`20
`
`one non-limiting example), photoreceptor degeneration, dry-form AMD, recessive cone'-rod dystrophy,
`
`exudative (or wet-form) age-related macular degeneration, cone-rod dystrophy, and retinitis pigmentosa.
`
`In further embodiments the mammal is an animal model for retinal degeneration.
`
`In further embodiments, are methods comprising multiple administrations of the effective
`
`(0016]
`amount of the agent which modulates RBP binding to TfR in said mammal. including furtb.er
`25 . embodiments in which (i) the time between multiple administrations is at least one wee~ (ii) the time·
`between multiple administrations is at least one day; and (iii) the compotmd is administered to the :
`mammal on a daily basis; or (iv) the compound is administered tO the mammal every 12 hours. Jn further
`or alternative embodiments, the method comprises a drug holiday, wherein the administration of the
`
`30
`
`compound is temporarily suspended or the dose of the compound being administered is tempo~ly
`reduced; at the end of the drug holiday, dosing of the compound is resumed. The length of the drug
`holiday can vary from 2 days to 1 year.
`[0017]
`
`In further embodiments are methods comprising adnrinistering at least one l!-d~tional agent
`
`selected from the group consisting of an inducer of nitric oxide production, an anti-inflammatory agent, a
`
`. physiologically acceptable antioxidant, a physiologically acceptable mineral, a negatively charged
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`phospholipid, a cayotenoid, a statin, an anti-angiogenic drug, a matrix metalloproteinase inlnOitor, 13-cis(cid:173)
`
`retin~ic acid (including derivatives of 13-cis-retinoic acid), 11-cis-retinoic acid (including.derivatives of
`
`11-cis-retinoic acid), 9-cis-retinoic acid (including derivatives of 9-cis-retinoic acid); and retinylamine
`
`deri"'&tives. In further embodiments:
`
`(a) the additional agent is an inducer of nitric oxide production, including embodiments in which
`
`the inducer of nitric oxide production is selected from the group consisting of citrulline,
`
`ornithine, nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-J,-arginine,
`nitrosylated N-hydroxy-L:..argilrlne, nitrosated L-homoaTginine and nitrosylated L(cid:173)
`
`homoarginine;
`
`(b) the additional agent is an anti-inflammatory agent, including embodimerits:in which the anti.(cid:173)
`inflammatory agent is selected from the group consisting of a non-steroidal ai)ti-
`
`. inflammatory drug, a lipoxygenase inhibitor, prednisone, dexamethasone, and a
`
`cyclooxygenase inlnbitor;
`(c) the additional agent is at least one physiologically acceptable antioxidant, including
`
`embodiments in which the physiologically acceptable antioxidant is selected from the group
`
`consisting of Vitamin C, Vitamin E, beta-carotene, Coenzyme Q, and 4-hydroxy-2,2,6,6-
`
`tetramethylpiperadine-N-oxyl, or embodiments in which (i) the at leaSt one physiologically
`acceptable antioxidant is administered with the agent which modulates RBP binding to TI'R
`in said mammal, or (ii) at le:ast two physiologically acceptable antioxidan~ are adininfstered
`with the agent which modulates RBP binding to ITR in said mammal;
`( d) the additional agent is at least one physiologically acceptable mineral, including
`embodiments in which the physiologically acceptable mineral is selected from the group
`
`consisting of a zinc (II) compound, a Cu(Il) compound, and a selenimn (II) compound, or
`
`embodiments further comprising administering to the mammal at least one physiologically
`
`acceptable antioxidant;
`(e) the additional agent is a negatively charged phospholipid, including embo~entS in which
`the negatively charged phospholipid is phospbatidylglycerol;
`
`(f) the additional agent is a carotenoid, including embodiments in which the caTotenoid is
`
`selected from the group consisting of lutein and zeaxanthin;
`
`(g) the additional agent is a statin, including embodiments in which the statin is selected from the
`
`group consisting of rosuvastatin, pitivastatin, simvastatin, pravastatin, cerivastatin,
`
`mevastatin, velostatin, fluvastatin, compactin, lovastatin, dalvastatin, fluindostatin,
`
`atorvastatin, atorvastatin calcium, and dihydrocompactin;
`
`(h) the additional agent is an anti-sngiogenic dnig, including embodiments in which the f:be anti(cid:173)
`
`angiogenic drug is Rhufab V2, Tryptophanyl-tRNA synthetase, an Anti-VEGF pegylated
`
`aptamer, Squalamine, anecortave acetate, Combretastatin A4 Prodrug, Macugen TM,
`mifePrlstone, subtenon triamcinolone acetonide, intravi~al crystalline triamcinolone
`acetonide, AG3340, fluocinolone acetonide, and VEGF-Trap;
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`(i) the additional agent is a matrix metalloproteinase inhibitor, including embodiments in which
`
`the matrix metalloproteinase inlu'bitor is a tissue inhibitors of metalloproteinases, ~­
`macroglobulin, a tetracycline, a hydroxamate, a chelator, a synthetic MMP ll:agment, a ·
`
`succinyl mercaptopurine, a phosphonamidate, and a hydroxaminic acid;
`
`5
`
`(j) the additional agent is a complement inlubitor, including by way of example only, antibodies
`
`against Cl, C2, C3, C4, CS, C6, C7, CS, and C9, such as those disclosed in.U.S. Pat. Nos.
`5,635~178; 5,843,884; 5,847,082; 5,853,722; and in Rollins et al.; Transplantationi 60:1284-.
`}292 (1995) (the contents of all of which are incorporated herein by reference);
`(k) the additional agent is a fish oil, including by way of ex&nple only, omega 3 fatty acids;
`
`10
`
`(1)
`
`the additional agent is 13-cu-retinoic acid (including derivatives of 13-cu-retinoic acid), 11-
`ciS-retinoic acid (including derivatives of 11-cu-retinoic acid), or 9-cu-retinoic acid
`
`15
`
`20
`
`(including derivatives of 9-cis-retinoic acid);
`
`(m) the additional agent is a retinylamine derivative, including an all-tra11s-retinylamine
`derivative, a 13-cu-retinylamine derivative, a 11-cu-retinylamine derivative, or a 9-cu(cid:173)
`
`retinylamine derivative;
`(n) the additional agent is administered (i} prior to the administration of the agent which
`modulates RBP binding to TIR in said mammal, (ii} subsequent to the administration of the
`agent which modulates RBP binding to TIR in said mammal, (iii) simultaneously with the
`administration of the agent which modulates RBP binding to TIR in said mammai, or (iv}
`both prior and subsequent to the administration of agent which modulates RBP binding to
`TIR in said mammal; or
`( o) the additional agent and agent which modulates RBP binding to TIR in said niammal, are
`administered in the same pharmaceutical composition.
`
`In further embodiments are methods comprising administering extracorporea1 meopheresis to
`
`[0018]
`the mammal. In further embodiments are methods comprising administering to the mammal a therapy
`
`25
`
`selected from the group consisting oflimited retinal translocation, photodynamic therapy, drus_en lasering,
`
`macular hole surgery, rnacular translocation surgery, Phi-Motion, Proton Beam Therapy, Retinal
`
`Detachment and Vitreous Surgery, Scleral Buckle, Submacular Smgery, Transpupillary Th~otherapy,
`
`Photosystem I therapy, MicroCurrent Stimulation, anti-inflammatory agents, RNA interference,
`.
`.
`.
`.
`administration of eye medications such as phospholine iodide oi echothiophate or carbonic anhydrase
`
`30
`
`inhibitors, microchip implantation, stem cell therapy, gene replacement therapy, n'bozyµie gene therapy,
`
`photoreceptor/retinal cells transplantation, and acupuncture.
`
`35
`
`[0019]
`Jn further embodiments are methods comprising the use oflaser photocoagulation to remove
`drusen from the eye of the mammal.
`In further embodiments are methods comprising administering to the manunai at least_once
`[0020]
`an effective amolnlt of a second agent which modulates RBP binding to TTR in said mammal, wherein
`the first compound is different from the second compound.
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`WO 2006/063128
`[0021)
`
`PCT/USWOS/044416
`fn further embodimentS, an apparatus capable of detecting and/or quantitating retinol-RBP-
`
`TTR complex formation is provided, wherein at least a portion of the TTR is fluorescently labeled. .
`
`[0022)
`
`Jn one embodiment, the retinyl derivative is N-(4-hydroxyphenyl)retinamide (&lso referied to
`
`herein as "IIPR" or "fenretinide" or "4-hydroxyphenylretinamide" or "hydroxyphenyl retinamide"), N-(4-
`5 methoxyphenyl)retinamide ("MPR"; the most prevalent metabolite of HPR), or ethylretinamid~. In ·
`another embodiment, the polybalogenated aromatic hydrocarbon is a hydroxylated polyhalogenated
`aromatic hydrocarbon metabolite. The hydroxylated polyhalogenated aromatic hydrocarbon metabolite
`may be a hy~xylated polychlorinated biphenyl metabolite. In yet another embodimen~ the diclo(enac
`analogue of the methods and compositions disclosed herein may be chosen from the group consisting of:
`
`10
`
`2-[(2,6-dichlorophenyl)amino]benzoic acid; 2-[(3,5-dichl0rophenyl)amino]benzoic aCid; 3,S,-dichloro-4-
`
`[(4-nitrophenyl)amino]benz.oic acid; 2-[(3,5-dichlorophenyl)amino]benzene acetic acid :and 2-[(2,6-
`
`dichloro-4-carboxylic acid-phenyl)amino]benzene acetic acid.
`[0023]
`
`fn other embodiments, the non-steroidal anti-inflammatory agent of the methods and
`
`15
`
`compositions disclosed herein may be tlufenamic acid, diflunisal, a diflunisal analogue, diclofenamic
`acid, indomethacin, niflumic acid or sulindac. Jn one embodiment, the diflunisal analogue may be 3',5'(cid:173)
`difluorobiphenyl-3-ol; 2' ,4'-diflurobiphenyl-3-carboxylic ~cid; 2' ,4'-difluorobiphenyl-4~~bo~lic acid;
`2' -fluorobiphenyl-3-carboxylic acid; 2' -fluorobiphenyl-4-carboxylic acid; 3' ,5 '-difluOf?bi~henyl-3-
`
`carboxylic acid; 3' ,5 '-difluorobiphenyl-4-carboxylic acid; 2 ',6' -difluorobiphenyl-3-carboxylic acid; .. 2' 6' -
`
`difluorobiphenyl-4-carboxylic acid; biphenyl-4-carboxylic acid; 4 'fluoro-4-hydroxybiphetiyl-3-carboxylic
`.
`.
`.
`acid; 2 '-fluoro-4-hydroxybiphenyl-3-carbo:xylic acid; 3 ',5 '-difluoro-4-hydroxybiphenyl-3~carboxylic
`
`20
`
`acid; 2 ',4 '-dichloro-4-hydroxybiphenyl-3-carboxylic acid; 4-hydrox:Ybiphenyl-3-carbozylic acid; 3 'S' -
`
`difluoro-4 'hydroxybiphenyl-3-carboxylic acid; 3 ',5'- difluoro-4 'hydrox.ybiphenyl-4-carboxylic acid;
`3 ',5' - dichloro-4 'hydroxybiphenyl-3-carboxylic acid; 3 ',5 '- dichloro-4 ;hydroxybipbenyl-4~arboxylic
`acid; 3 ',5' -dichloro-3-fonnylbiphenyl; 3 ',5'-dichloro-2-formylbiphenyl; 2' ,4 '-dichlorobiphenyl-3-
`carboxylic acid; 2' ,4 '-dichlorobiphenyl-4-carboxylic acid; 3 ',5'-dichlorobiphenyl-3-yl-methanol; 3 ',s• -
`dichlorobiphenyl-4-yl-~thanol; or 3 ',5'-dichlorobiphenyl-2-yl-methanol.
`[0024]
`Jn other embodiments, the flavonoid of the methods and compositions disclosed herein may
`be 3-methyl-4 • ,6-dihydroxy-3 ',5' -dibromoflavone or 3 ',5'-dt"bromo-2 ',4,4' ,6-tetrahydr~urone. In yet
`
`another embodiment, the cardiac agent of the methods and compositions disclosed herein is milrinone .
`. .
`[0025]
`Jn another embodiment, the small molecule of the methods and COIIlpositions disclosed herein
`is N-phenylanthranilic acid, methyl red, mordant orange I, bisarylanline, N-benzyl-p-aminobenzoic aci~
`:furosamide, apigenin, resveratrol, biarylamine or dibenzofuran. Jn one embodiment, the thyroid hormone
`
`analogue may be thyroxine-propionic acid, thyroxine-acetic acid, or SKF94901.
`
`[0026]
`The methods and compositions disclosed herein also provide for modulating RBP,or TfR
`levels or activity in a mammal comprising administering to the mammal at least o.nce an effective amount
`of an agent which increases the clearance rate of RBP or TI'R in said mammal, wherein said modulation
`of RBP or TI'R levels or activity reduces the formation of all-trans retinal in an eye of a mammal In one
`embodiment, the agent.may be chosen from the group consisting of: a retinyl derivative, a
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`CFAD V. UPENN
`IPR2015-01836
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`WO 2006/063128
`PCT/US2005/044416
`polyhalogenated aromatic hydrocarbon, a thyroid hormone agonist, a thyroid honnone antagonist,
`
`diclofenac, a diclofenac analogue, a small molecule compound, an endocrine hormone analogue, a
`flavonoid, a non-steroidal anti-inflammatory drug, a bivalent inlubitor, a cardiac agent, a peptidomimetic,
`an aptamer, and an anbbody.
`Jn one embodiment, the retinyl derivative is a compound having the structure:
`
`[0027]
`
`5
`
`XI
`I
`(I),
`Rt
`; R 1 is (CHR 2>x-L 1-R3
`wherein X1 is selected from the group consisting ofNR2
`, 0, S, CHR2
`, wherein x is
`0, 1, 2, or 3; L1 is a single bond or-C(O)-; R2 is a moiety selected from the group consisting ofH, (Cr
`C4)alkyl, F, (C1-C4)fluoroalkyl, (C1-C4)alkoxy, -C(O)OH, -C(O)-NH2, -(C1-C4)alkylamine, -C(O)-(Ci-
`C4)alkyl, -C(O)-(C1-C4)fluoralkyl, -C(O)-(C1~)alkylamine, and -C(O)-(CrCJalkoxy; and R3 is Hor a
`moiety, optionally substituted with 1-3 independently selected substituents, selected froµi the group
`
`consisting of (C:z-C,)alkenyl, (C:z-C,)alkynyl, aryl, (C3-(4)cycloalkyl, (C5-(4)cycloalkenyl; and a
`heterocycle; or an active metabolite, or a pharmaceutically acceptable prodrug or solvate thereof.
`
`(0028]
`
`In one embodiment, the retinyl derivative is a compound having the structure:
`0
`
`,(1
`11
`R (II};
`
`whereinX1 is selected from the group consisting ofNR2, 0, S, CHR.2
`; R 1 is (CHR.2)x-L1-R3
`, wherein xis
`0, 1, 2, or 3; L1 is a single bond or -C(O)-; R2 is a moiety selected from the group consisting ofH, (Cr
`C4)alkyl, F, (C1-C4)fluoroalkyl, (C1-C4)alkoxy, -C(O)OH, -C(O)-NH2, -(C1-C4)allcylamine, -C(O)-(C1-
`C4)alkyl, -C(O)-(C1-C4)fluoroalkyl, -C(O)-(C1-~)alkylamine, and -C(O)-(C,~)alkoxy; and R3 is H or a
`moiety, optionally substituted with 1-3 independently selected substituents, selected from the gr<>up
`consisting of (C:z-C7)alkenyl, (C:z-C,)alkynyl, aryl, (~-C1)cycloalkyl, (Cs-C1)cycloallceriyl, :and a
`heterocycle; or an active metabolite, or a pharmaceutically acceptable prodrug or solvate thereof.
`, wherein R2 is Hor (C1-C,.)alkyl; (b) xis' O; (c) x ts 1
`Jn further embodiments (a) X 1 is NR2
`[0029]
`and L 1 is--c(O)-; (d) R3 is an optionally substituted aryl; (e) R3 is an optionally substituted he~oaryl; (f)
`X 1 is NH and R3 is an optionally substituted aryl, including yet further embodiments in ~hich (i) the aryl
`group has one substituent, (ii) the aryl group has one substituent selected from the group consisting of
`
`halogen, OH, O(C1-C4)alkyl, NH(C1-C4)alkyl, O(C1-C4)fluoroalkyl, and N[(C1-C4)alkyl]2, (iii).the aryl
`group bas one substituent, which is OH, (v) the aryl is a phenyl, or (vi) the aryl is naphthyl; (g) the
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`CFAD V. UPENN
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`

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`WO 2006/063128
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`PCT/US2005/044416
`
`d"
`.
`compoun is
`
`' ¢ . ·~bo1·
`
`OH
`
`, or an active mei.a.
`
`1te, or a p
`
`hann.
`
`. al.I
`
`•
`
`aceutic y
`
`acceptable prodrug or solvate thereof; (h) the compound is 4-hydroxyphenylretinamide,:or a metabolite,
`
`or a pharmaceutically acceptable prodrug or solvate thereof; (i) the compound is 4-
`methoxyphenylretinamide, or G) 4-oxo fenretinide, or a metabolite, or a pharmaceutically acceptable
`
`5
`
`prodrug or solvate thereof.
`
`[0030]
`
`In further embodiments, the administration of a compound of Formula (II) is used to treat
`
`ophthabnic conditions by lowering the levels of serum retinol in the body of a patient In further
`.
`embodiments (a) the effective amount of the compound is systemically administered to the mainmal; (b) :
`
`the effective am01.mt of the compound is administered orally to the mammal; (c) the effective amo\Dlt of
`
`10
`
`the compound is intravenously administered to the mammal; ( d) the effective amount of the compound is
`ophthalmically administered to the manunal; (e) the effective amount of the compound is administered by
`iontophoresis; or (f) the effective amount of the compound is administered by injection to the mammal.
`
`15
`
`20
`
`In further embodiments the mammal is a hmnan, including embodiments wherein (a) the
`[0031]
`human is a carrier of the mutantABCA.4 gene for StargardtDisease or the human bas a mutantELOV4
`gene for Stargardt Disease, or has a genetic variation in complement factor H associated with age-related
`
`macular degeneration, or (b) the human has an ophthabnic condition or trait selected from the woup
`
`consisting of Stargardt Disease, recessive retinitis pigmentosa, geographic atrophy (of which scotoma is
`
`one non-limiting example), photoreceptor degeneration, dry-formAMo, recessive cone-rod dystrophy,
`
`exudative (or wet-form) age-related macular degeneration, cone-rod dystrophy, and retinitis pigmentosa.
`In further embodiments the mammal is an animal model for retinal degeneration.
`In further embodiments, are methods comprising multiple administrations of the effective
`[0032]
`
`amount of the agent which increases the clearance rate of RBP or 1TR in said mammal, including further
`
`embodiments in which (i) the time between multiple administrations is at least one wee~ (ii) the time
`
`between multiple administrations is at least one day; and (iii) the compound is administered to the.
`
`25 mammal on a daily basis; or (iv) the compound