How chaperone molecules work

Chaperone

Chaperone molecules like the one Amicus Therapeutics is developing for Pompe disease help damaged or malformed proteins fold into a usable shape.

Chaperone

Normal protein

Damaged protein

Normal protein

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included MDA grantee Alan Beggs at Children’s Hospital and Harvard Medical School in Boston, have demonstrated that gene transfer may be an effective approach to treating myotubular myopathy (MTM), which results from the lack of a protein called myotubularin.

A single injection of myotubularin genes into a leg muscle in myotubu-larin-deficient mice resulted in a large increase in muscle volume and force, as well as a normalization of microscopic appearance of the muscle fibers in the injected muscle.

The researchers, who published their results online April 22 in Human Molecular Genetics, used modified adeno-associated viruses (AAVs) as delivery vehicles for the genes. AAV vehicles have been used in human gene-transfer trials to target muscle fibers.

They note that their results “ indicate that gene therapy by local [myo-tubularin] transfer in skeletal muscle improves the strength of the targeted muscle in a mouse model of myotubular myopathy and might open novel strategies for treating this disorder.”

Protecting mitochondria
with Debio-025 helped
mice with two forms of MD

A compound that protects cellular structures known as mitochondria from damage is beneficial in mice with two forms of muscular dystrophy, investigators have found.

Jeffery Molkentin at Cincinnati Children’s Hospital Medical Center, and colleagues, including H. Lee Sweeney at the University of Pennsylvania, who has MDA funding for related work, published their findings online March 16 in Nature Medicine.

First, the investigators analyzed mice with two forms of MD that also were bred not to produce a protein called cyclophilin D.

The lack of cyclophilin D prevented much of the damage that would have been expected in the delta-sarcogly-can-deficient mouse model of type 2F limb-girdle MD (LGMD2F) and the laminin-2-deficient mouse model of congenital MD. This is due to its apparent protection of mitochondria, the energy-producing structures inside cells.

In both these forms of MD, as well as in Duchenne MD (DMD), the membrane surrounding each muscle fiber allows excess calcium to flow into muscle cells, which, in part through cyclophilin D’s actions, causes swelling and destruction of mitochondria. Without cyclophilin D, the researchers found, the mitochondria of MD-affect-ed mice demonstrated resistance to this type of damage.

They next tested Debio-025 (made by DebioPharm of Lausanne, Switzerland), a known inhibitor of cyclophilin D, in the mouse model of LGMD2F and in mice missing the dystrophin protein that have a disease resembling DMD.

The mitochondria of these mice also were protected. In addition, the DMD mice treated with Debio-025 from four to 10 weeks of age showed better muscle-fiber organization and less scar tissue than was seen in untreated DMD mice.

Similar effects were seen in the LGMD2F mice treated with Debio- 025 from age four to age 10 weeks, and these mice also showed better cardiac muscle health than did untreated LGMD2F mice. The researchers say their results suggest that protecting muscle-fiber mitochondria by inhibiting cyclophilin D could become a new approach for treating muscular dystrophies that are associated with defective muscle-fiber membranes.

Company to develop
‘chaperone’ molecule
for Pompe disease

A new approach to treating Pompe disease (acid maltase deficiency),

a genetic muscle disorder resulting from a lack of functional acid maltase enzyme, has yielded encouraging findings to researchers at Amicus Therapeutics ( www.amicustherapeutics. com), a biopharmaceutical company in Cranbury, N.J.

The company presented results of tests in patients’ cells and in healthy volunteers of its experimental compound AT2220 at the American College of Human Genetics annual meeting in Phoenix in March. (Amicus presented an earlier stage of its research to MDA’s Translational Research Advisory Committee.)

AT2220 is a small, orally administered molecule that Amicus terms a “pharmacological chaperone,” one of several the company is developing to treat genetic diseases.

Pharmacological chaperones, like their natural counterparts in cells, stick to specific proteins and help them fold into the correct three-dimensional shape. Many genetic diseases, including Pompe disease, can be caused at least some of the time by genetic mutations that result in improper folding of a protein. (In Pompe disease, the protein is the acid maltase enzyme, made from the acid maltase gene.) An improperly folded enzyme doesn’t locate itself or function properly.

The Amicus researchers collected blood and skin samples from 30 people with Pompe disease ( 26 adults, three children and one infant) due to a variety of mutations in the acid maltase gene.

They then tested cells from these samples to see whether AT2220 could increase the level of functional acid maltase.