Active Ingredient of Blood Pressure Treatment Boosts ERT’s Efficacy in Skeletal Muscles, Mouse Study Suggests

Active Ingredient of Blood Pressure Treatment Boosts ERT’s Efficacy in Skeletal Muscles, Mouse Study Suggests

Adding carvedilol, the active compound of a blood pressure medicine, to enzyme replacement therapy (ERT) for Pompe disease can improve its effectiveness in reaching and strengthening skeletal muscles, a study in mice suggests.

This finding, “Evaluation of antihypertensive drugs in combination with enzyme replacement therapy in mice with Pompe disease” was published in Molecular Genetics and Metabolism.

At present, enzyme replacement therapy (ERT) is the only effective treatment for Pompe disease, a rare genetic disorder caused by the absence or deficiency of the acid alpha-glucosidase (GAA) enzyme.

When GAA activity is low, a sugar molecule called glycogen accumulates inside cells, damaging organs and tissues throughout the body, but primarily skeletal muscle, smooth muscle, and cardiac muscle. If left untreated, the accumulation of glycogen in cardiac and skeletal muscle leads to severe and progressive muscular weakness, risking heart and respiratory failure.

There is, however, a major limitation in ERT. Skeletal muscle is less accessible to it, meaning the therapy has trouble getting into this type of muscle cell. Skeletal muscle’s poor response to ERT has been attributed to a serious lack of a protein receptor — called cation-independent mannose-6-phosphate receptor (CI-MPR) — on its cells.

Animal studies suggest that an active compound common to blood pressure medications (with work to control hypertension) could increase the uptake of ERT by muscle cells, by increasing the amount of muscle (muscle hypertrophy), and therefore the amount of CI-MPR.

Investigators at Duke University evaluated the effects of ERT with and without three anti-hypertensive agents: carvedilol, losartan, and propranolol. All these compounds have different ways of working, or mechanisms of action, in the body. They experimented using a mouse model of Pompe disease called the GAA knockout (absent) mouse.

Animals were assigned to one of seven groups: no treatment, ERT alone, ERT with carvedilol, ERT with losartan, ERT with propranolol, or to only losartan or carvedilol. Drugs were given to the mice in drinking water, and one week after treatment initiation, recombinant human GAA was given by injection every week for a month. Five days following the last GAA injection, scientists examined the animals’ cardiac and muscle function.

The team reported that “carvedilol uniquely increased muscle strength, while losartan uniquely decreased heart rate.” GAA activity was also found to be significantly higher in the heart following either losartan or propranolol being added to enzyme replacement therapy, compared to mice left untreated as a control group.

Both carvedilol or propranolol significantly increased GAA activity in the animals’ quadriceps, the muscles in the front of the thigh, compared to control mice. “However, only carvedilol administration significantly increased GAA activity in quadriceps, in comparison with ERT alone,” the scientists wrote.

These findings indicate that the greatest rise in enzymatic activity occurred in response to carvedilol, the active substance in the blood pressure medication Coreg. Carvedilol is a beta-blocker that relaxes the smooth muscle that makes up blood vessels, leading to an overall reduction in blood pressure.

Because more than half (seven of 13) of the mice given losartan, either alone or in combination with ERT, died during the study, researchers thought this active molecule potentially toxic in Pompe, and suggested physicians should be mindful of it when prescribing high blood pressure medications to Pompe patients.

“Currently we demonstrated unique toxicity from the administration of losartan in mice with Pompe disease,” the researchers wrote.

Because of the benefits seen in diseased mice given carvedilol during ERT, they recommended the compound be studied in a clinical trial in patients.

“Carvedilol was well-tolerated, and the ability to use a β-blocker [beta-blocker] in patients that will not interfere with ERT would be highly valuable for clinical use in patients with Pompe since they often require a β-blocker to mitigate disease-associated hypertension,” the investigators concluded.

“A clinical trial of carvedilol in patients with Pompe disease should be considered to further evaluate its usefulness.”

With over three years of experience in the medical communications business, Catarina holds a BSc. in Biomedical Sciences and a MSc. in Neurosciences. Apart from writing, she has been involved in patient-oriented translational and clinical research.
Total Posts: 3
Margarida graduated with a BS in Health Sciences from the University of Lisbon and a MSc in Biotechnology from Instituto Superior Técnico (IST-UL). She worked as a molecular biologist research associate at a Cambridge UK-based biotech company that discovers and develops therapeutic, fully human monoclonal antibodies.
×
With over three years of experience in the medical communications business, Catarina holds a BSc. in Biomedical Sciences and a MSc. in Neurosciences. Apart from writing, she has been involved in patient-oriented translational and clinical research.
Latest Posts
  • treatment combinations
  • infantile-onset case report
  • diagnosis

Leave a Comment

Your email address will not be published. Required fields are marked *