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Precursor N-acetylgalactosamine-4 sulfatase, methods of treatment using said enzyme and methods for producing and purifying said enzyme

a technology of n-acetylgalactosamine and sulfatase, which is applied in the fields of biochemistry and molecular biology, can solve the problems of affecting learning and development, no acceptable clinical dosage or medical formulation, and substantial morbidity and mortality, and achieves high purity

Inactive Publication Date: 2005-12-29
BIOMARIN PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a method for treating diseases caused by a deficiency in N-acetylgalactosamine-4-sulfatase (ASB) by administering a therapeutically effective amount of highly purified N-acetylgalactosamine-4-sulfatase (ASB) in a precursor form. The invention also includes methods for transferring a nucleic acid encoding all or a part of the ASB gene into host cells in vivo. The therapeutically effective amount of ASB is preferably administered as a recombinant human ASB preparation. The invention also provides pharmaceutical compositions containing recombinant human ASB for treating a deficiency in ASB. The invention further includes methods for increasing ASB activity in humans by gene therapy or transfer of an exogenous hASB gene.

Problems solved by technology

Distinct from MPS I, MPS VI is not typically associated with progressive impairment of mental status, although physical limitations may impact learning and development.
BMT is not universally available for lack of a suitable donor and is associated with substantial morbidity and mortality.
Likewise, no acceptable clinical dosages or medical formulations have been provided.

Method used

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  • Precursor N-acetylgalactosamine-4 sulfatase, methods of treatment using said enzyme and methods for producing and purifying said enzyme
  • Precursor N-acetylgalactosamine-4 sulfatase, methods of treatment using said enzyme and methods for producing and purifying said enzyme
  • Precursor N-acetylgalactosamine-4 sulfatase, methods of treatment using said enzyme and methods for producing and purifying said enzyme

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Experimental program
Comparison scheme
Effect test

example 1

Clinical Evaluation with Recombinant Human N-acetylgalactosamine-4-sulfatase

Summary

[0095] The indication for recombinant human N-acetylgalactosamine-4-sulfatase (rhASB) is the treatment of MPS VI, also known as Maroteaux-Lamy Syndrome. We propose a clinical development program for rhASB consisting of an initial open-label clinical trial that will provide an assessment of weekly infusions of the enzyme for safety, pharmacokinetics, and initial response of both surrogate and defined clinical endpoints. The trial will be conducted for a minimum of three months to collect sufficient safety information for 5 evaluable patients. At this time, should the initial dose of 1 mg / kg not produce a reasonable reduction in excess urinary glycosaminoglycans or produce a significant direct clinical benefit, the dose will be doubled and maintained for an additional three months to establish safety and to evaluate further efficacy.

Objectives

[0096] Our primary objective is to demonstrate safety o...

example 2

[0105] A comprehensive review of the available information for the MPS VI cat and relevant pharmacology and toxicology studies is presented below: Enzyme replacement therapy has been established as a promising treatment for a variety of inherited metabolic disorders such as Gaucher Disease, Fabry Disease and Mucopolysaccharidosis I. In some of these disorders a natural animal model offers the ability to predict the clinical efficacy of human treatment during pre-clinical studies. This was found to be true in MPS I (canine model). With this in mind, studies have been performed with the MPS VI cat prior to the commencement of human studies for this disease. Sufficient safety and efficacy data exist to proceed with a clinical trial in human MPS VI patients.

[0106] Studies of rhASB MPS VI cats indicate that no cat has died as a result of drug administration. As predicted, experiments in MPS VI cats also indicate that rhASB uptake is dependent on the presence of mannose 6-phosphate modif...

example 3

Distribution and Feasibility

[0112] An initial study was performed to document enzyme uptake and distribution, and to serve as a pilot study of potential endpoints for future efficacy studies (Crawley, et al., J. Clin. Invest. 97.1864-1873 (1996)). Recombinant human ASB was administered by bolus injection to affected cats once per week or once every two weeks at 0.5 up to 1.5 mg / kg. Evaluation of one untreated MPS VI cat (Cat D), and one normal cat provided the values from which comparisons were drawn. The data from the one untreated cat was further supported by historical assessment of 38 additional untreated cats. The acute uptake and distribution studies were conducted in normal cats using an immune assay technique that allowed the detection of human ASB in the presence of normal cat enzyme.

[0113] The major conclusions of these studies demonstrated wide uptake of enzyme with the expected predominance of liver and spleen uptake as observed in other enzyme replacement studies in M...

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Abstract

The present invention provides a highly purified recombinant, human precursor N-acetylgalactosamine-4-sulfatase and biologically active mutants, fragments and analogs thereof as well as pharmaceutical formulations comprising highly purified recombinant human precursor N-acetylgalactosamine-4-sulfatase. The invention also provides methods for treating diseases caused all or in part by deficiencies in human N-acetylgalactosamine-4-sulfatase including MPS VI and methods for producing and purifying the recombinant precursor enzyme to a highly purified form.

Description

[0001] This is a continuation-in-part of U.S. Ser. No. 10 / 290,908 filed Nov. 7, 2002 and a continuation-in-part of U.S. Ser. No. 10 / 658,699 [Attorney Docket No. 30610 / 30013A] filed Sep. 9, 2003, which in turn is a divisional of U.S. Ser. No. 09 / 562,427 filed May 1, 2000, each of which is incorporated by reference herein in its entirety.FIELD OF THE INVENTION [0002] The present invention is in the field of clinical medicine, biochemistry and molecular biology. The present invention features therapeutics and methods for treating mucopolysaccharidosis VI as well as production and purification procedures for producing such therapeutics. BACKGROUND OF THE INVENTION [0003] MPS VI (Maroteaux-Lamy syndrome) is a lysosomal storage disease in which the affected patients lack the enzyme N-acetylgalactosamine-4-sulfatase (ASB). The enzyme metabolizes the sulfate moiety of glycosaminoglycan (GAG) dermatan sulfate (Neufeld, et al., “The mucopolysaccharidoses” The Metabolic Basis of Inherited Dise...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/00A61K38/46A61K48/00C12N9/16
CPCA61K48/00C12N9/16C12Y301/06012B01D15/3828B01D15/327B01D15/3804A61K38/00
Inventor QIN, MINMINZECHERLE, GARYCHAN, WAI-PANFITZPATRICK, PAULSWIEDLER, STUARTHENSTRAND, JOHNWENDT, DANCHEN, LINSTARR, CHRISTOPHER
Owner BIOMARIN PHARMA INC
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