Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for... – Hydrolase
Reexamination Certificate
1999-03-11
2002-10-01
Prouty, Rebecca E. (Department: 1652)
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
Hydrolase
C435S183000, C435S193000, C536S023100, C536S023200, C536S023400, C424S094100, C424S094610
Reexamination Certificate
active
06458574
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods and compositions for the treatment of &agr;-galactosidase A deficiency.
BACKGROUND OF THE INVENTION
Fabry disease is an X-linked inherited lysosomal storage disease characterized by severe renal impairment, angiokeratomas, and cardiovascular abnormalities, including ventricular enlargement and mitral valve insufficiency. Fabry disease also affects the peripheral nervous system, causing episodes of agonizing, burning pain in the extremities. Fabry disease is caused by a deficiency in the enzyme &agr;-galactosidase A (&agr;-Gal A). &agr;-Gal A is the lysosomal glycohydrolase that cleaves the terminal &agr;-galactosyl moieties of various glycoconjugates. Fabry disease results in a blockage of the catabolism of the neutral glycosphingolipid, ceramide trihexoside (CTH), and accumulation of this enzyme substrate within cells and in the bloodstream.
Due to the X-linked inheritance pattern of the disease, most Fabry disease patients are male. Although severely affected female heterozygotes have been observed, female heterozygotes are often asymptomatic or have relatively mild symptoms (such as a characteristic opacity of the cornea). An atypical variant of Fabry disease, exhibiting low residual &agr;-Gal A activity and either very mild symptoms or apparently no other symptoms characteristic of Fabry disease, correlates with left ventricular hypertrophy and cardiac disease. Nakano et al.,
New Engl. J. Med
. 333: 288-293 (1995). A reduction in &agr;-Gal A may be the cause of such cardiac abnormalities.
The cDNA and gene encoding human &agr;-Gal A have been isolated and sequenced. Human &agr;-Gal A is expressed as a 429-amino acid polypeptide, of which the N-terminal 31 amino acids are the signal peptide. The human enzyme has been expressed in Chinese Hamster Ovary (CHO) cells (Desnick et al., U.S. Pat. No. 5,356,804; Ioannou et al.,
J. Cell Biol
. 119: 1137 (1992)); and insect cells (Calhoun et al., WO 90/11353).
However, current preparations of &agr;-Gal A have limited efficacy. Methods for the preparation of &agr;-Gal A with relatively high purity depend on the use of affinity chromatography, using a combination of lectin affinity chromatography (concanavalin A (Con A) Sepharose®) and affinity chromatography based on binding of &agr;-Gal A to the substrate analog N-6-aininohexanoyl-&agr;-D-galactosylamine coupled to a Sepharose® matrix. See, e.g., Bishop et al.,
J. Biol. Chem
. 256: 1307-1316 (1981). The use of proteinaceous lectin affinity resins and substrate analog resins is typically associated with the continuous leaching of the affinity agent from the solid support (Marikar et al.,
Anal. Biochem
. 201: 306-310 (1992), resulting in contamination of the purified product with the affinity agent either free in solution or bound to eluted protein. Such contaminants make the product unsuitable for use in pharmaceutical preparations. Bound substrate analogs and lectins can also have substantial negative effects on the enzymatic, functional, and structural properties of proteins. Moreover, &agr;-Gal A produced by the methods in the prior art is rapidly eliminated by the liver.
Thus, a need remains in the art for a purification protocol using conventional chromatography resins, which are readily available in supplies and quality suitable for large-scale commercial use, and which produces an &agr;-Gal A preparation that is free of affinity agent. In addition, a need remains in the art for &agr;-Gal A preparations with an increased circulating half-life and increased uptake in specific tissues other than liver.
SUMMARY OF THE INVENTION
The invention provides highly purified &agr;-Gal A preparations, and various methods for purifying the &agr;-Gal A glycoforms. The invention also provides &agr;-Gal A preparations with altered charge and methods for making those preparations. Charge alterations are achieved by increasing the sialic acid content of &agr;-Gal A and/or by increasing the phosphorylation of &agr;-Gal A. The invention further provides &agr;-Gal A preparations that have an extended circulating half-life in a mammalian host, and methods for making same. Finally, the present invention further provides methods and dosages for administering an &agr;-Gal A preparation to a subject. The &agr;-Gal A preparations of the present invention will be useful for treatment of individuals with Fabry disease or atypical variants of Fabry disease, e.g., specific populations of Fabry patients with predominantly cardiovascular abnormalities, such as ventricular enlargement, e.g., left ventricular hypertrophy (LVH), and/or mitral valve insufficiency, or Fabry patients with predominantly renal involvement.
REFERENCES:
patent: 4407957 (1983-10-01), Lim
patent: 4740365 (1988-04-01), Yukimatsu et al.
patent: 4764376 (1988-08-01), Hirsch et al.
patent: 5179023 (1993-01-01), Calhoun et al.
patent: 5356804 (1994-10-01), Desnick et al.
patent: 5401650 (1995-03-01), Desnick et al.
patent: 5654007 (1997-08-01), Johnson et al.
patent: 5733761 (1998-03-01), Treco et al.
patent: 5750376 (1998-05-01), Weiss et al.
patent: 5780014 (1998-07-01), Eljamal et al.
patent: 5780045 (1998-07-01), McQuinn et al.
patent: 5789247 (1998-08-01), Ballay et al.
patent: 5798113 (1998-08-01), Dionne et al.
patent: 5804413 (1998-09-01), DeLuca
patent: 5814607 (1998-09-01), Patton
patent: 5858751 (1999-01-01), Paulson et al.
patent: WO 90/11353 (1990-10-01), None
patent: WO 94/12618 (1994-06-01), None
patent: WO 95/06478 (1995-03-01), None
patent: WO 98/11206 (1998-03-01), None
International Search Report for PCT/US00/06118.
Written Opinion for PCT/US00/06118.
Medin et al., “Correction in trans for Fabry disease: Expression, secretion, and uptake of . . . ”, Jul. 1996, Proc.Natl.Acad.Sci.USA, vol. 93; 7917-7922.
Ashwell & Harford,Ann. Rev. Biochem. 51: 531-554 (1982).
Beutler,New Engl. J. Med. 325:1354-1360 (1991).
Bishop et al.,J. Biol. Chem. 256: 1307-1316 (1981).
Cuozzo et al.,J. Biol. Chem. 273: 21069-21076 (1998).
Delgado et al.,Crit. Rev. Ther. Drug Carrier Syst. 9:249-304 (1992).
Diment et al.,J. Leukocyte Biol. 42: 485-490 (1987).
Edwards et al.,Science276: 1868-1872 (1997).
Francis et al.,Int. J. Hematol. 68(1): 1-18 (1998).
Grammatikos et al.,Biotechnol. Progr. 14:410-419 (1998).
Hantzopolous et al.,Gene57:159 (1987).
Herment in et al,Glycobiology6: 217-230 (1996).
Ihara et al.,J. Biochem. (Tokyo) 113: 692-698 (1993).
Ioannou et al.,J. Cell Biol. 119: 1137-1150 (1992).
Isidoro et al.,Eur. J. Biochem. 191: 591-597 (1990).
Kinstler et al.,Pharm. Res. 13: 996-1002 (1996).
Korner et al.,Proc. Natl. Acad. Sci. USA95: 13200-13205 (1998).
Kornfeld & Mellman,Ann. Rev. Cell. Biol. 5: 483-525 (1989).
Kukuruzinska & Lennon,Crit. Rev. Oral. Biol. Med. 9: 415-48 (1998).
LeDonne et al.,Arch. Biochem. Biophys. 224: 186 (1983).
Lemansky et al.,J. Biol. Chem. 262: 2062 (1987).
Marikar et al.,Anal. Biochem. 201: 306-310 (1992).
Matsuura et al.,Glycobiology8: 329-339 (1998).
Mizushima et al.,Nucl. Acids Res. 18: 5322 (1990).
Nakano et al.,New Engl. J. Med. 333: 288-293 (1995).
Rijcken et al.,Biochem.J. 305: 865-870 (1995).
Sburlati et al.,Biotechnical. Progr. 14: 189-192 (1998).
Ven der Bliek et al.,Cancer Research48: 5927-5932 (1988).
Borowski Marianne
Daniel Peter F.
Kinoshita Carol M.
Schuetz Thomas J.
Selden Richard F
Fish & Richardson PC
Hutson Richard
Prouty Rebecca E.
Transkaryotic Therapies Inc.
LandOfFree
Treatment of a &agr;-galactosidase a deficiency does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Treatment of a &agr;-galactosidase a deficiency, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Treatment of a &agr;-galactosidase a deficiency will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2996032