A beta-blocker, propranolol, decreases the efficacy from enzyme replacement therapy in Pompe disease

Han, Sang-oh; Pope, Rand; Li, Songtao; Kishnani, Priya S.; Steet, Richard; Koeberl, Dwight D.

doi:10.1016/j.ymgme.2015.09.012

Cited by 11 publications

(13 citation statements)

References 30 publications

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“…4B). Furthermore, administration of propranolol, a beta-blocker that increased the uptake of GAA but reduced efficacy from ERT [16], failed to reduce LC3-II (Fig. 4A,C).…”

Section: Resultsmentioning

confidence: 99%

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Salmeterol enhances the cardiac response to gene therapy in Pompe disease

Han

Koeberl

2016

Molecular Genetics and Metabolism

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Enzyme replacement therapy (ERT) with recombinant human (rh) acid α-glucosidase (GAA) has prolonged the survival of patients. However, the paucity of cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle, where it is needed to take up rhGAA, correlated with a poor response to ERT by muscle in Pompe disease. Clenbuterol, a selective β2 receptor agonist, enhanced the CI-MPR expression in striated muscle through Igf-1 mediated muscle hypertrophy, which correlated with increased CI-MPR (also the Igf-2 receptor) expression. In this study we have evaluated 4 new drugs in GAA knockout (KO) mice in combination with an adeno-associated virus (AAV) vector encoding human GAA, 3 alternative β2 agonists and dehydroepiandrosterone (DHEA). Mice were injected with AAV2/9-CBhGAA (1E+11 vector particles) at a dose previously found to be partially effective at clearing glycogen storage from the heart. Heart GAA activity was significantly increased by either salmeterol (p<0.01) or DHEA (p<0.05), in comparison with untreated mice. Furthermore, glycogen content was reduced in the heart by treatment with DHEA (p<0.001), salmeterol (p<0.05), formoterol (p<0.01), or clenbuterol (p<0.01) in combination with the AAV vector, in comparison with untreated GAA-KO mice. Wirehang testing revealed that salmeterol and the AAV vector significantly increased performance in comparison with the AAV vector alone (p<0.001). Similarly, salmeterol with the vector increased performance significantly more than any of the other drugs. The most effective individual drugs had no significant effect in absence of vector, in comparison with untreated mice. Thus, salmeterol should be further developed as adjunctive therapy in combination with either ERT or gene therapy for Pompe disease.

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“…4B). Furthermore, administration of propranolol, a beta-blocker that increased the uptake of GAA but reduced efficacy from ERT [16], failed to reduce LC3-II (Fig. 4A,C).…”

Section: Resultsmentioning

confidence: 99%

“…However, this phenomenon has been observed following administration of ERT with propranolol [16]. The observed improvement in muscle function might be attributable to greater cardiac function following biochemical correction of the heart, although cardiac function was not directly evaluated in either of these studies.…”

Section: Discussionmentioning

confidence: 97%

Salmeterol enhances the cardiac response to gene therapy in Pompe disease

Han

Koeberl

2016

Molecular Genetics and Metabolism

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“…Beta-2 adrenergic agonists, most notably albuterol, have been used to increase muscle mass and strength in normal individuals and in patients with muscular dystrophy [9] , [10] . Beta-2 agonists were demonstrated to increase the expression of cation-independent mannose-6-phosphate receptor (CI-MPR) and CI-MPR-mediated uptake of rhGAA in murine Pompe disease [11] , and beta-blockers decreased the efficacy of rhGAA therapy [12] . A pilot clinical trial also showed improvement in muscle power in a 6-minute walk test (6MWT) in adult patients with LOPD [13] .…”

Section: Introductionmentioning

confidence: 99%

Albuterol as an adjunctive treatment to enzyme replacement therapy in infantile-onset Pompe disease

Chien

Hwu

Lee

et al. 2017

Molecular Genetics and Metabolism Reports

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BackgroundEarly initiation of enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase is an effective treatment for patients with infantile-onset Pompe disease (IOPD) but cannot prevent a slow progression of myopathy. Albuterol has been shown to be helpful in adult patients with Pompe disease, and therefore, we administered an open-label adjunctive therapy with albuterol in IOPD patients undergoing ERT.MethodsFourteen patients, aged 2 to 12 years, were enrolled in this study; all of them had a disease onset before 12 months of life, and 13 of them were ambulatory because of early initiation of ERT. All patients received albuterol (also referred to as salbutamol) 12 mg daily for 26 weeks. The outcome measurements included a 6-minute walk test, four-stair climb test (SCT), the standing/walking/running/jumping domains of Gross Motor Function Measure-88, speech quality, serum creatine kinase, and urinary glucose tetrasaccharide. Outcome and safety measurements were evaluated at baseline, and at 1, 3, and 6 months (26 weeks) after entering the trial.ResultsAfter a period of 26 weeks, among the 12 patients who were able to complete the SCT, the median time needed decreased by 22% (p = 0.034). Other parameters inconsistently improved in a variety of individuals. Eleven adverse events, including nausea, urinary frequency, and tachycardia, were potentially related to the study drug, but all were mild and disappeared after a brief drug withdrawal. One patient was actively withdrawn from the trial because of poor compliance.ConclusionsThe results of our study suggest that albuterol showed a good safety profile as an adjunctive treatment in our IOPD cohort, although the benefits are limited.

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“…Decreased glycogen content has correlated with lower ventricle mass in treated GAA-KO mice 18 . Left ventricle mass was significantly decreased by administration of 3E+9 vg in comparison with PBS-injected controls (Figure 3C), both in groups of mice treated as infants (p < 0.001) and as adults (p < 0.001).…”

Section: Resultsmentioning

confidence: 88%

Comparisons of Infant and Adult Mice Reveal Age Effects for Liver Depot Gene Therapy in Pompe Disease

Han

McCall

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Pompe disease is caused by the deficiency of lysosomal acid α-glucosidase (GAA). It is expected that gene therapy to replace GAA with adeno-associated virus (AAV) vectors will be less effective early in life because of the rapid loss of vector genomes. AAV2/8-LSPhGAA (3 × 1010 vector genomes [vg]/mouse) was administered to infant (2-week-old) or adult (2-month-old) GAA knockout mice. AAV vector transduction in adult mice significantly corrected GAA deficiency in the heart (p < 0.0001), diaphragm (p < 0.01), and quadriceps (p < 0.001) for >50 weeks. However, in infant mice, the same treatment only partially corrected GAA deficiency in the heart (p < 0.05), diaphragm (p < 0.05), and quadriceps (p < 0.05). The clearance of glycogen was much more efficient in adult mice compared with infant mice. Improved wire hang test latency was observed for treated adults (p < 0.05), but not for infant mice. Abnormal ventilation was corrected in both infant and adult mice. Vector-treated female mice demonstrated functional improvement, despite a lower degree of biochemical correction compared with male mice. The relative vector dose for infants was approximately 3-fold higher than adults, when normalized to body weight at the time of vector administration. Given these data, the dose requirement to achieve similar efficacy will be higher for the treatment of young patients.

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A beta-blocker, propranolol, decreases the efficacy from enzyme replacement therapy in Pompe disease

Cited by 11 publications

References 30 publications

Salmeterol enhances the cardiac response to gene therapy in Pompe disease

Salmeterol enhances the cardiac response to gene therapy in Pompe disease

Albuterol as an adjunctive treatment to enzyme replacement therapy in infantile-onset Pompe disease

Comparisons of Infant and Adult Mice Reveal Age Effects for Liver Depot Gene Therapy in Pompe Disease

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