Amicus Therapeutics (Cranbury, NJ) found itself in the news earlier this month when the FDA agreed to review the company’s new drug application for their investigational therapy to treat Fabry’s disease. The drug under consideration, migalastat, has already been approved by the European Medicines Agency. It belongs to a small, but growing class of therapeutics known as pharmacological chaperones that properly fold improperly folded proteins that cause disease.

Let’s take a look at which chaperones are on the dance floor and find out the steps they are taking to treat disease caused by proteins.


Chaperone proteins are proteins that assist in the correct folding and assembly of other proteins. Many of the proteins produced by our cells require chaperone proteins to ensure their correct molecular structure.

A pharmacological chaperone is a small molecule drug that targets specific misfolded proteins and encourages them to fold correctly.

Protein misfolding plays a role in many different rare diseases, including enzyme deficiencies like Fabry’s and the related Niemann-Pick disease, as well as Huntington’s disease, and some cases of amyotrophic lateral sclerosis (ALS). Some of the mutations in the genetic disease cystic fibrosis (CF) involve misfolded proteins. Diseases caused by misfolded proteins that disrupt cellular function are sometimes called proteopathies, where proteo = protein, pathy = disease.


A type of lysosomal storage disorder, Fabry’s disease involves the inability to process certain types of lipids (fats), because they lack functional versions of critical enzymes, resulting in a range of symptoms, including kidney, heart, and skin disorders. The enzyme in question here, galactosidase, helps to break down glycolipids — lipids with a carbohydrate attached. Production of functional galactosidase enzyme is limited because of mutations in the galactosidase gene that cause the enzyme to be misfolded and therefore non-functional.

The only Fabry’s disease treatment on the market in the U.S. is Fabrazyme, which is made by Genzyme (Cambridge, MA). Fabrazyme is an enzyme-replacement therapy: since the patients don’t make enough functional galactosidase enzyme, scientists produce it in the lab using cells that have been genetically engineered to produce the enzyme, which is then purified and injected into patients.


Amicus’ drug migalastat, if approved, would be the first small molecule treatment for Fabry’s. The potential availability of swallowing a drug (vs. injecting) would give those with Fabry’s another drug delivery option.

In the lab, migalastat binds to and inhibits galactosidase. In the body, this high affinity is taken advantage of by migalastat binding to mutated galactosidase during the process of folding, where it then shifts the folding towards the correct conformation. The now correctly folded protein makes its way to a cellular compartment known as the lysosome, where it carries out its job of digesting lipids. The inside of the lysosome has an acidic pH, which causes migalastat to disassociate, leaving behind a functional galactosidase enzyme for the body to pick up and use.

Fabry’s is caused by a variety of different mutations within the galactosidase gene; not all of them are amenable to treatment with migalastat. Amicus scientists estimate that between 35% to 50% of patients will be responsive to migalastat.


Another disease that can be traced to protein misfolding is cystic fibrosis. CF is a genetic disease caused by one of several possible mutations in the gene encoding the “cystic fibrosis transmembrane conductance regulator” (CTFR) protein. The CTFR protein is critical for the production of sweat, digestive fluids, and mucus.

The most common mutation, responsible for about two-thirds of CF cases, results in a protein that is so misfolded, it never makes it to the cell surface where it is required to do its job. Vertex Pharmaceuticals’ (Boston, MA) drug lumacaftor serves as a pharmacological chaperone for these proteins, assisting them with correct folding so that they can make it to the cell surface. Lumacaftor is one piece of the CF puzzle; it is often used in combination with other therapies to fight various aspects of the disease.


Instead of creating pharmacological chaperones, another approach to getting mutated proteins to fold correctly is to stimulate diseased cells to produce greater amounts of natural chaperone proteins. This can be done by identifying small molecules that induce cells to express heat shock proteins, a common class of cellular chaperones (described below). Two companies following this approach are Orphazyme (Copenhagen, Denmark) and Chaperone Therapeutics (Research Triangle Park, NC).

Orphazyme’s lead product, arimoclomal, has completed Phase II clinical testing for amyotrophic lateral sclerosis (ALS) associated with mutations in the gene for superoxide dismutase 1 (SOD1) enzyme; sporadic inclusion body myositis (sIBM), a rare muscular atrophy disease; and Niemann-Pick disease, a lysosomal storage disorder similar to Fabry’s disease.

Chaperone Therapeutics has a drug in preclinical development for Huntington’s disease, which is associated with disordered folding of the huntingtin protein.


The largest family of naturally-occurring chaperone proteins are called “heat shock proteins” because they were first discovered as part of a cellular response to heat shock — exposure to a higher than normal temperature. These proteins were later discovered to be induced in response to other types of cellular stress such as ultraviolet light exposure or wound healing. It’s thought that these cellular stressors can disrupt protein folding, and the production of heat shock protein chaperones can help to counteract the disruption.

Pharmacological chaperones that activate or mimic these protective proteins may prove to be the fresh new approach that can make a difference in a whole range of different diseases.

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