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Methods and compositions for increasing n-acetylglucosaminidase activity in the CNS

a technology of nacetylglucosaminidase and cns, which is applied in the field of methods and compositions for increasing nacetylglucosaminidase activity in the cns, can solve the problems of pathological buildup of glycosaminoglycans and little impact on the effects of disease, and achieve the effect of retaining naglu enzyme activity

Inactive Publication Date: 2021-01-07
ARMAGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a method for treating a deficiency of alpha-N-acetylglucosaminidase (NAGLU) in the central nervous system by delivering a therapeutically effective amount of a fusion antibody that targets the insulin receptor and NAGLU. The fusion antibody is a human insulin antibody that binds to the insulin receptor and acts as a molecular Trojan horse to ferry NAGLU into the brain. The method involves systemically administering the fusion antibody to a subject in need, resulting in the delivery of NAGLU enzyme activity to the brain. The therapeutic effect of the method is the restoration of NAGLU enzyme activity in the brain, which can be measured by the amount of NAGLU enzyme in the brain. The amount of NAGLU enzyme delivered to the brain can be normalized per 50 kg body weight.

Problems solved by technology

An insufficient level of these enzymes causes a pathological buildup of glycosaminoglycans in, e.g., peripheral tissues, and the CNS.
However, systemically administered recombinant enzymes do not cross the blood brain barrier (BBB), and therefore would have little impact on the effects of the disease in the CNS.

Method used

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  • Methods and compositions for increasing n-acetylglucosaminidase activity in the CNS
  • Methods and compositions for increasing n-acetylglucosaminidase activity in the CNS
  • Methods and compositions for increasing n-acetylglucosaminidase activity in the CNS

Examples

Experimental program
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Effect test

example 1

n and Functional Analysis of HIR Ab-GUSB Fusion Protein

[0205]The lysosomal enzyme mutated in MPS-VII, also called Sly syndrome, is β-glucuronidase (GUSB). MPS-VII results in accumulation of glycosoaminoglycans in the brain. Enzyme replacement therapy (ERT) of MPS-VII would not likely be effective for treatment of the brain because the GUSB enzyme does not cross the BBB. In an effort to re-engineer human GUSB to cross the BBB, a HIR Ab-GUSB fusion protein project was initiated.

[0206]Human GUSB cDNA corresponding to amino acids Met1-Thr651 of the human GUSB protein (NP_000172), including the 22 amino acid signal peptide, and the 18 amino acid carboxyl terminal propeptide, was cloned by reverse transcription (RT) polymerase chain reaction (PCR) and custom oligodexoynucleotides (ODNs). PCR products were resolved in 1% agarose gel electrophoresis, and the expected major single band of ˜2.0 kb corresponding to the human GUSB cDNA was isolated. The cloned human GUSB was inserted into a euk...

example 2

n and Functional Analysis of HIR Ab-GCR Fusion Protein

[0213]The lysosomal enzyme, mutated in Gaucher's disease (GD) is β-glucocerebrosidase (GCR). Neuronopathic forms of GD affect the CNS, and this results in accumulation of lysosomal inclusion bodies in brain cells, owing to the absence of GCR enzyme activity in the brain. Enzyme replacement therapy (ERT) of GD is not an effective for treatment of the brain because the GCR enzyme does not cross the BBB. In an effort to re-engineer human GCR to cross the BBB, a HIR Ab-GCR fusion protein project was engineered, expressed, and tested for enzyme activity. The human GCR cDNA corresponding to amino acids Ala40-Gln536 of the human GCR protein (NP_000148), minus the 39 amino acid signal peptide, was custom synthesized by a commercial DNA production company. The GCB cDNA was comprised of 1522 nucleotides (nt), which included the GCB open reading frame, minus the signal peptide through the TGA stop codon. On the 5′-end, a StuI restriction en...

example 3

ion of Human HIR Ab Heavy Chain-NAGLU Fusion Protein Expression Vector

[0217]The lysosomal enzyme mutated in MPS-IIIB is NAGLU. MPS-IIIB results in accumulation of heparan sulfate in the brain. Enzyme replacement therapy of MPS-IIIB is not effective for treatment of the brain because the NAGLU enzyme does not cross the BBB, as described by DiNatale et al (2005): Treatment of the mouse model of mucopolysaccharidosis type IIIB with lentiviral-NAGLU vector,” Biochem. 1, 388: 639-646. NAGLU was fused to the HIR Ab in order to develop a bifunctional molecule capable of both crossing the BBB and exhibiting enzymatic activity. In one embodiment the amino terminus of the mature NAGLU is fused to the carboxyl terminus of each heavy chain of the HIR Ab (FIG. 2).

[0218]It was unclear whether the enzymatic activity of the NAGLU would be retained when it was fused to the HIR Ab. The experience with IgG-GUSB and IgG-GCR fusion proteins described in Examples 1 and 2 illustrate the unpredictable natu...

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Abstract

Provided herein are methods and compositions for treating a subject suffering from an enzyme deficiency in the central nervous system (CNS). The bifunctional fusion antibody provided herein comprise an antibody to an endogenous blood brain barrier (BBB) receptor and an enzyme deficient in mucopolysaccharidosis IIIB (MPS-IIIB). The fusion antibodies provided herein comprise alpha-N-acetylgulcosaminidase (NAGLU). The methods of treating an enzyme deficiency in the CNS comprise systemic administration of a fusion antibody provided herein.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 14 / 994,067, which claims priority to U.S. Provisional Patent Application No. 62 / 103,506, filed Jan. 14, 2015, which applications are incorporated herein by reference in their entirety.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Apr. 12, 2017, is named 28570-713_301_SL.txt and is 89,235 bytes in size.BACKGROUND OF THE INVENTION[0003]Mucopolysaccharidosis (MPS) III, also called MPS-III or Sanfilippo syndrome, is an inherited metabolic disease that mainly affects the central nervous system (CNS). MPS III is caused by defects in enzymes needed to break down long chains of sugar molecules called glycosaminoglycans. There are four main types of MPS-III. Type A (MPS-IIIA) is caused by a defect in the lysosom...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/28C12N9/24
CPCC07K16/2869C12N9/2402A61K38/00C07K2317/94C07K2317/14C12Y302/0105A61K2039/505C07K2319/00C07K16/28C07K16/2803C07K2317/92C07K2317/565C07K2317/24C07K16/18C07K16/26C07K19/00C07K2319/30A61K47/64A61K45/00A61K47/6849A61K2039/545C07K16/46A61K47/642A61K39/395A61K47/65A61K38/47C12N9/96C12Y302/01076C07K2317/55C12N9/48C12Y301/06013C12N15/09C07K2317/567C07K1/22C12N9/2465
Inventor PARDRIDGE, WILLIAM M.BOADO, RUBEN J.
Owner ARMAGEN INC
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