Combination therapy for treating protein deficiency disorders

Abstract

This application provides methods of improving protein replacement therapy by combining protein replacement therapy with active site-specific chaperones (ASSC) to increase the stability and efficiency of the protein being administered. The application further provides stable compositions comprising the purified protein and an ASSC, and methods of treatment by administering the compositions.

Description

[0001] This application is a divisional of U.S. application Ser. No. 11 / 317,404, filed on Dec. 23, 2005 (pending), which is a continuation of U.S. application Ser. No. 10 / 771,236, filed on Feb. 2, 2004 (abandoned), which claims priority benefit from U.S. Provisional Application Ser. No. 60 / 444,136, filed Jan. 31, 2003 (abandoned), each of which is incorporated by reference herein in its entirety.FIELD OF THE INVENTION [0002] This application provides methods of improving protein replacement therapy by combining protein replacement therapy with active site-specific chaperones (ASSC) to increase the stability and efficiency of the protein being administered. The application further provides compositions comprising the purified protein and an ASSC. BACKGROUND Protein Deficiency [0003] Proteins are synthesized intracellularly according to the genomic nucleotide sequence of a particular gene through transcription, translation, and other processes. Protein deficiency can be caused by a m...

AI Technical Summary

Benefits of technology

[0018] The present invention provides a method for enhancing the stability of a purified protein, which method comprises contacting the protein in a pharmaceutically acceptable carrier with an active site-specific chaperone.

[0020] The present invention also provides a method of increasing in vitro the shelf-life of a protein by contacting the protein in a pharmaceutically acceptable carrier with an active site-specific chaperone.

[0022] The present invention further provides a method of extending the half-life and prolonging the activity in vivo of a purified protein in an individual who has been administered the protein in a pharmaceutically acceptable carrier, which method comprises contacting the protein with an active site-specific chaperone in a pharmaceutically acceptable carrier.

[0028] The invention also provides a method for enhancing the stability of a mutant, endogenous protein that is deficient due to defective folding or processing in the ER concurrently with protein replacement therapy. Stability and, hence, activity of the endogenous protein will be enhanced concurrently with the increased stability of the administered replacement protein that corresponds to the mutant protein.

[0029] The invention further provides a method for increasing the production of recombinant protein by non-mammalian host cells by contacting the host cell in a medium comprising an ASSC for the protein.

Problems solved by technology

One of the main complications with protein replacement therapy is attainment and maintenance of therapeutically effective amounts of protein due to rapid degradation of the infused protein.

Protein replacement therapy has several additional caveats, such as difficulties with large-scale generation, purification and storage of properly folded protein, obtaining glycosylated native protein, generation of an anti-protein immune response, and inability of protein to cross the blood-brain barrier in diseases having significant central nervous system involvement.

Although promising, this approach is also limited by technical difficulties such as the inability of vectors to infect or transduce dividing cells, low expression of the target gene, and regulation of expression once the gene is delivered.

These heritable disorders are characterized by deficiencies in lysosomal enzymes that catalyze the breakdown of glycolipids in cells, resulting in an abnormal accumulation of lipids which disrupts cellular function.

This approach is also limited in that glycolipids are necessary for biological function, and excess deprivation may cause adverse effects.

If there are too few or too many glycolipids, the ability of the neuron to send signals is impeded.

In vivo, protein folding is complicated, because the combination of ambient temperature and high protein concentration stimulates the process of aggregation, in which amino acids normally buried in the hydrophobic core interact with their neighbors non-specifically.

Certain DNA mutations result in amino acid substitutions that further impede, and in many cases preclude, proper folding of the mutant proteins.

The high doses of this class of compounds required for efficacy makes them difficult or inappropriate to use clinically, although they are useful for the biochemical examination of folding defect of a protein intracellularly.

These compounds also lack specificity.

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