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Published in final edited form as: Mol Genet Metab. 2011 Nov 11;105(2):221–227. doi: 10.1016/j.ymgme.2011.11.005

β2 Agonists Enhance the Efficacy of Simultaneous Enzyme Replacement Therapy in Murine Pompe Disease

Dwight D Koeberl 1,*, Songtao Li 1, Jian Dai 1, Beth L Thurberg 2, Deeksha Bali 1, Priya S Kishnani 1
PMCID: PMC3264842  NIHMSID: NIHMS338200  PMID: 22154081

Abstract

Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) has improved clinical outcomes in patients with Pompe disease; however, the response of skeletal muscle and the central nervous system to ERT has been attenuated. The poor response of skeletal muscle to ERT has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR), which mediates receptor-mediated uptake of rhGAA. Hence the ability of adjunctive therapy with β2-agonists to increase CI-MPR expression in skeletal muscle was evaluated during ERT in murine Pompe disease with regard to reversal of neuromuscular involvement. Mice with Pompe disease were treated with weekly rhGAA injections (20 mg/kg) and a selective β2-agonist, either albuterol (30 mg/l in drinking water) or low-dose clenbuterol (6 mg/l in drinking water). Biochemical correction was enhanced by β2-agonist treatment in both muscle and the cerebellum, indicating that adjunctive therapy could enhance efficacy from ERT in Pompe disease with regard to neuromuscular involvement. Intriguingly, clenbuterol slightly reduced muscle glycogen content independent of CI-MPR expression, as demonstrated in CI-MPR knockout/GAA knockout mice that were otherwise resistant to ERT. Thus, adjunctive therapy with β2 agonists might improve the efficacy of ERT in Pompe disease and possibly other lysosomal storage disorders through enhancing receptor-mediated uptake of recombinant lysosomal enzymes.

Keywords: Mannose-6-phosphate receptor, enzyme replacement therapy, adeno-associated virus, acid alpha-glucosidase, acid maltase, Pompe disease, glycogen storage disease type II

INTRODUCTION

Infantile-onset Pompe disease results from the deficiency of lysosomal acid-α-glucosidase (GAA) and affects the heart and skeletal muscle primarily, causing death early in childhood from cardiorespiratory failure if untreated. Current therapy in the form of enzyme replacement therapy (ERT) has prolonged ventilator-free survival and muscle strength in patients with Pompe disease; however, the limitations of ERT have become increasingly evident and many patients eventually become ventilator-dependent on ERT. The enzyme dosages required for ERT in Pompe disease range up to 100-fold greater than those for other lysosomal disorders, which can be attributed at least in part to the poor uptake of recombinant human (rh) GAA by skeletal muscle associated with low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR). These limitations must be overcome to address the limitations of replacement therapy, be it ERT or gene therapy. Preclinical and clinical data suggest that paucity of CI-MPR reduced the uptake of GAA by Pompe disease cells [1–3]. The relevance of CI-MPR-mediated uptake during ERT was demonstrated by the increased efficacy of rhGAA that was modified to increase mannose-6-phosphate content in mice with Pompe disease [4; 5]. Consistent with a deficiency of the uptake and lysosomal targeting of GAA, Pompe disease patient fibroblasts were found to be deficient in CI-MPR recycling and uptake of rhGAA was impaired [3].

A lack of complete efficacy from ERT has been observed in long term survivors with infantile Pompe disease. Even in patients with a good response to ERT, a residual residual motor weakness (neck flexor weakness, dorsiflexor weakness, mypathic facies, ptosis and strabismus) has been observed. Respiratory insufficiency is observed especially in those started late [6]. CNS involvement as indicated by the prevalence of sensorineural hearing loss, hypernasal speech, with a flaccid dysarthria and aspiration risk suggestive of bulbar involvement is commonly observed in long term survivors [7]. Strabismus and ptosis have been observed frequently among children with Pompe disease following long-term ERT [8]. Each of these abnormalities demonstrated a lack of complete efficacy from ERT. Patients with late-onset Pompe disease have severe pulmonary insufficiency which may progress to respiratory failure while receiving ERT [9]. Many individuals with late-onset Pompe disease have residual gait abnormalities despite adherence to ERT, indicating a relative lack of response of limb-girdle and leg muscles [10]. Autopsy of infantile patients has revealed glycogen accumulation in Purkinje cells of the cerebellum, neurons of the cerebral cortex, motor neurons of the spinal cord and in vascular smooth muscle cells of the CNS vasculature, all of which may contribute to the neurological deficits observed in these patients [11].

Dosages for ERT in Pompe disease are up to 100-fold greater than those in other lysosomal disorders, which has been attributed to the large mass of skeletal muscle (~40% of body weight), and to the low abundance of CI-MPR on skeletal muscle. The paucity of CI-MPR in adult mammals’ muscle has underscored the concept that CI-MPR is limiting for ERT in Pompe disease. Previously, low levels of CI-MPR were demonstrated in skeletal muscle of GAA-KO mice, specifically in muscles comprised primarily of type II myofibers [2; 12]. We have evaluated the impact of CI-MPR-mediated uptake of GAA upon ERT in CI-MPR knockout (KO)/GAA-KO mice. The essential role of CI-MPR was emphasized by the lack of efficacy for either ERT [13] or gene therapy [14], as demonstrated by markedly reduced biochemical correction of GAA deficiency and of glycogen accumulations in CI-MPR-KO/GAA-KO mice, in comparison with administration of the same therapy in GAA-KO mice. Clenbuterol was previously demonstrated to increase the expression of the insulin-like growth factor 2 receptor (identical to CI-MPR) in muscle of mice [5]. Initial results revealed that high-dose clenbuterol, a β2-agonist, enhanced CI-MPR expression and increased efficacy from GAA replacement therapy, thereby confirming the key role of CI-MPR with regard to replacement therapy in Pompe disease [13]. Biochemical correction improved in multiple skeletal muscles indicating that adjunctive therapies might enhance the response to ERT in Pompe disease [13].

Clenbuterol treatment clearly enhanced the biochemical correction of muscle from ERT in Pompe disease, which led us to further evaluate the efficacy of β2-agonist administration in GAA-KO mice. Dose-related side effects have been observed in association with β2-agonist treatment; therefore, we administered clenbuterol at a lower dose in combination with ERT in GAA-KO mice. A second β2-agonist, albuterol, was evaluated similarly at a high dose. Both of these agents increased the clearance of glycogen in the muscle of GAA-KO mice; moreover, the uptake of rhGAA in the cerebral and cerebellar hemispheres of the brain was increased in association with increased clearance of glycogen in the brain of GAA-KO mice. These data further demonstrated the efficacy of adjunctive therapy with selective β2-agonists in a classical lysosomal storage disorder, Pompe disease, and suggested that this strategy might be effective in other lysosomal storage disorders that affect the brain.

MATERIALS AND METHODS

ERT in mice with Pompe disease

Tolerant GAA-KO mice [15] and CI-MPR-KO/GAA-KO mice [13] were administered four weekly doses of 20 mg/kg rhGAA and sacrificed 7 days after the last injection. Selected tissues were collected for GAA enzyme activity and glycogen content analyses. All animal procedures were done in accordance with Duke University Institutional Animal Care and Use Committee-approved guidelines. GAA activity and glycogen content analyses, Rotarod testing, and Western blot detection of CI-MPR was performed as described [13]. Wirehang testing was performed with a 0.5 cm mesh hardware cloth fixed to an 8 by 10 inch frame. Mice were placed on the wire mesh, which was slowly inverted 6 inches over a cage containing paper bedding. The latency, or time until the mouse fell into the cage, was recorded.

Statistical analyses

Comparison of two groups was assessed by a homoscedastic Student T-test. A p-value <0.05 was considered to be statistically significant.

RESULTS

Enhanced efficacy from simultaneous ERT and β2-agonist administration: motor function, GAA uptake and glycogen clearance

Two β2-agonists were evaluated in combination with ERT, clenbuterol and albuterol. The dose of clenbuterol was reduced 5-fold from the concentration studied previously [13], to 6 mg/l in drinking water, while albuterol was evaluated at the higher dose (30 mg/l in drinking water). Groups of 3 month-old immune tolerant GAA-KO mice were treated with four weekly doses of rhGAA (20 mg/kg body weight), with or without concurrent β2-agonist treatment. Tolerant GAA-KO mice do not form anti-GAA antibodies or develop hypersensitivity reactions during ERT with rhGAA, in contrast to non-tolerant GAA-KO mice that developed both of these complications during ERT [2; 16].

The efficacy of β2-agonist treatment was demonstrated by an increase in Rotarod and wirehang latency following low-dose clenbuterol treatment. Low-dose clenbuterol significantly increased Rotarod latency following 4 weeks of combined treatment, in comparison with ERT alone (Fig. 1A; p<0.05), although the mean latency was significantly elevated at week 0 in the clenbuterol-treated group without reaching statiscal significance (p =0.47). Low-dose clenbuterol did not significantly increase wirehang latency (not shown). The weight of the gastrocnemius increased in mice treated with combined treatment, in comparison with GAA-KO mice treated with ERT alone (Fig. 1B), which suggested that muscle hypertrophy was stimulated as described by clenbuterol [17].

Fig. 1. Muscle function and biochemical evaluatoin following low-dose clenbuterol treatment.

Fig. 1

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GAA-KO mice were administered four weekly doses of rhGAA (20 mg/kg), and treated with clenbuterol (n=7), or untreated (n=6 or 3). (A) Rotarod latency at the indicated times. (B) Weight of gastrocnemius. (C) GAA enzyme levels and (D) glycogen content were evaluated in skeletal muscle, including the quadriceps, gastrocnemious (Gastroc.), tibialis anterior (Tib. Ant.), EDL, and soleus. Mean +/− standard deviation are shown. Statistically significant alterations associated with clenbuterol treatment indicated (* = p<0.05; ** = p<0.001).

The efficacy of β2-agonist treatment was further demonstrated by an enhanced biochemical correction of striated muscle and the liver. GAA activity was not significantly increased in the heart or skeletal mucle following low-dose clenbuterol treatment (Fig. 1C); however, the glycogen content was reduced significantly in all striated muscles evaluated with the exception of tibialis anterior by clenbuterol treatment, in comparison with ERT alone (Fig. 1D). These biochemical data indicated that clenbuterol treatment increased the clearance of lysosomal glycogen without elevating GAA activity in the muscle homogenate.

Treatment with albuterol increased Rotarod latency only at 5 weeks, in comparison with GAA-KO mice treated with ERT alone (Fig. 2A), which suggested a later-onset effect from albuterol than for clenbuterol at a low (Fig. 1A) or high dosage [13]. irehang latency increased significantly following combined treatment, in comparison with ERT alone (Fig. 2B). GAA activity was increased only in the tibialis anterior by albuterol treatment, in comparison with ERT alone (Fig. 2C); however, albuterol significantly reduced the glycogen content in the quadriceps and liver, in comparison with ERT alone (Fig. 2D), despite the lack of increased GAA activity in those tissues (Fig. 2B). These biochemical data were consistent with the effect of low-dose clenbuterol, which increased the clearance of glycogen without significantly increasing GAA activity in the muscle homogenate (Fig. 1C–D).

Fig. 2. Muscle function and biochemical evaluatoin following albuterol treatment.

Fig. 2

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GAA-KO mice were administered four weekly doses of rhGAA (20 mg/kg), and treated with albuterol (n=4) or untreated (n=6 or 3). (A) Rotarod latency at the indicated times. (B) Wirehang latency. (C) GAA enzyme levels and (D) glycogen content were evaluated in skeletal muscle, including the quadriceps, gastrocnemious (Gastroc.), tibialis anterior (Tib. Ant.), EDL, and soleus. Mean +/− standard deviation are shown. Statistically significant alterations associated with clenbuterol treatment indicated (* = p<0.05; ** = p<0.001).

Enhanced biochemical correction in the cerebellum following ERT and β2-agonist administration

The effect of β2-agonist treatment was further evaluated by biochemical evaluation of the brain. The cerebral and cerebellar hemispheres were analyzed separately, and a trend toward increased GAA activity was demonstrated in the cerebellum following clenbuterol (p=0.08) and albuterol (p=0.09) treatment (Fig. 3A). Glycogen content was reduced significantly by either clenbuterol or albuterol treatment in the cerebellum, but not in the cerebrum (Fig. 3B).

Fig. 3. Decreased glycogen content in the cerebellum following β-2 agonist administration.

Fig. 3

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Cerebral and cerebellar hemispheres were analyzed 5 weeks following the initiation of ERT. Groups of mice were treated with clenbuterol (n=6), albuterol (n=4) or untreated (n=6). (A) GAA enzyme levels and (B) glycogen content. Statistically significant alterations associated with clenbuterol treatment indicated (* = p<0.05; ** = p<0.001).

Histopathology was performed to examine brain involvement, and glycogen accumulations were detected in the cerebellum with ERT alone (Fig. 4A, arrows). Either albuterol (Fig. 4B) or clenbuterol (Fig. 4C) reduced the glycogen staining in the cerebellum, in comparison with ERT alone (Fig. 4A). Furthermore, both clenbuterol and albuterol increased CI-MPR expression in the cerebellum for the majority of mice analyzed (Fig. 5A). The median signal for CI-MPR increased by 38% following clenbuterol treatment (p=0.07), whereas it increased only by 20 % following albuterol treatment (Fig. 5B).

Fig. 4. Decreased glycogen accumulation in the cerebellum following β-2 agonist administration.

Fig. 4

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Periodic-acid Schiff staining for glycogen in paraffin-embedded sections of the cerebellum. Original magnification 400x. (A) ERT alone. (B) ERT with concurrent albuterol treatment. (C) ERT with concurrent clenbuterol treatment. Glycogen accumulations indicated (arrows).

Fig. 5. CI-MPR expression in the cerebellum following β-2 agonist administration.

Fig. 5

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(A) Western blot detection of CI-MPR and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in the cerebellum of mice, treated with ERT (lanes 1–3), ERT and clenbuterol (lanes 4–6), or ERT and albuterol (lanes 7–9). Each lane represents an individual mouse. (B) Densitometry for Western blot detection of CI-MPR, normalized to GAPDH, in mice from (A).

β2-agonists increased efficacy in absence of CI-MPR expression

The mechanism of β2-agonist treatment was further evaluated in GAA-KO mice with muscle-specific knockout of CI-MPR (“double-knockout”; DKO). DKO mice should have a decreased response to the combination of β2-agonist treatment, if CI-MPR modulates the effect of β2-agonists upon ERT. Clenbuterol was administered at the high dose (30 mg/l in drinking water) in combination with ERT, which previously enhanced the biochemical correction of skeletal muscle and the Rotarod performance in GAA-KO mice following 4 weeks of treatment [13]. Rotarod latency was not significantly elevated in DKO mice following combined treatment, in comparison with clenbuterol alone (Fig. 6A); however, wirehang latency was following combined treatment, in comparison with clenbuterol alone (Fig. 6B). The latter effect indicated that ERT might have an effect on muscle strength, independent of CI-MPR expression.

Fig. 6. Muscle function and biochemical evaluatoin following clenbuterol treatment in DKO mice.

Fig. 6

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DKO mice were administered four weekly doses of rhGAA (20 mg/kg) and treated with high-dose clenbuterol (n=7), clenbuterol alone (6), or untreated (n=7). Mean +/− standard deviation are shown. Statistically significant alterations associated with clenbuterol treatment indicated (* = p<0.05; ** = p<0.001). (A) Rotarod latency at the indicated times. (B) Wirehang latency. (C) GAA enzyme levels were evaluated in skeletal muscle, including the quadriceps, gastrocnemious (Gastroc.), and EDL. (D) Glycogen content for DKO mice treated with ERT and clenbuterol, or untreated DKO mice. (E) Glycogen content for DKO mice treated with clenbuterol, or untreated DKO mice. (F) Glycogen reduction for GAA-KO mice [13] or DKO mice treated with ERT and clenbuterol.

We previously hypothesized that a second receptor increased the uptake of rhGAA independent of CI-MPR, because DKO mice had detectably increased GAA activity in heart and quadriceps that following ERT [13]. Therefore, biochemical correction was evaluated in both the heart and skeletal muscle of DKO mice. GAA activity was not significantly increased following administration of either ERT with clenbuterol or clenbuterol alone, in comparison with untreated DKO mice (Fig. 6C). However, the glycogen content of the heart and skeletal muscle was significantly reduced following combination treatment, in comparison with untreated DKO mice (Fig. 6D). Clenbuterol alone slightly reduced the glycogen content of only quadriceps and extensor digitorum longus (EDL) (Fig. 6E). In order to estimate the relative contribution of CI-MPR to the effect of clenbuterol, we calculated the reduction in glycogen content achieved by combination therapy in both GAA-KO and DKO mice (Fig. 6F). A greater degree of glycogen clearance was demonstrated in GAA-KO mice, in comparison with DKO mice, in the heart, diaphragm, and quadriceps.

DISCUSSION

The modulating effect of CI-MPR has now been confirmed by analyzing the efficacy from GAA replacement therapy in mice with Pompe disease in combination with β2-agonist treatment. The up-regulation of CI-MPR by treatment with clenbuterol previously enhanced the response to ERT in the muscle of GAA-KO mice [13]. In the current study glycogen storage was reduced in the quadriceps, gastrocnemius, andEDL) following clenbuterol treatment, which are skeletal muscles comprised primarily of type II myofibers that have typically resisted the therapeutic effects of ERT in Pompe disease [12]. Furthermore, adjunctive treatment with either albuterol or clenbuterol reduced glycogen storage in the cerebellum, which is a site of glycogen accumulation in infantile Pompe disease [11]. The the combined data from low-dose clenbuterol and albuterol demonstrated that biochemical correction was enhanced despite the unchanged GAA activity in tissues, as reflected by reduced glycogen content following β2-agonist treatment. These data suggested that trafficking of GAA to lysosomes and activation were increased in the setting of increased CI-MPR expression. We previously demonstrated that CI-MPR deficiency impaired the efficacy of muscle-targeted gene therapy, indicating that activation of GAA was dependent upon receptor-mediated intracellular trafficking in mice with Pompe disease [14]. The effect of clenbuterol was dependent upon CI-MPR expression, because the degree of glycogen reduction was much higher in GAA-KO mice than in DKO mice for the heart, diaphragm, and quadriceps (80–97% versus 33–41%, respectively). The degree of glycogen reduction was low for both strains of mice in the gastrocnemius and EDL (<40%). Therefore, β2-agonist treatment promises to improve the response of major muscles to ERT in Pompe disease.

Clenbuterol stimulated skeletal muscle hypertrophy in rodent models by increasing expression of Igf-I and Igf-II [18; 19]. Clenbuterol administration was associated with increased muscle weight in the limb muscles, including gastrocnemius as seen in the current study [20–22]. The expression of the Igf-II receptor, identical to CI-MPR, was increased in the hypertrophied masseter muscle following clenbuterol treatment [17]. Taken together, these data suggest that the mechanism for enhanced efficacy from replacement therapy by the addition of clenbuterol is the expression of CI-MPR by type II myofibers that were previously unresponsive to ERT [2; 12]. Administration of high-dose clenbuterol alone in GAA-KO mice did not reduce the glycogen content of skeletal muscle (not shown), indicating that its effectiveness will be primarily as an adjunctive therapy.

Clenbuterol has been prescribed for the treatment of asthma due to bronchodilator effects, and it has been used illicitly by performance athletes for its hypertrophic effects upon muscle [18]. Side effects include muscle tremor, tremor and insomnia [18]. Caution has been urged due to the relatively high dosages used to achieve muscle hypertrophy in rodent models, and this study used approximately 42 μg/kg/day, given an estimated water consumption for mice of 7 ml/day. However, dosing as low as 5 μg/kg/day increased muscle force generation in horses, indicating that much lower doses might be effective [23]. Oral clenbuterol was well-tolerated in a long-term study of four Duchenne muscular dystrophy patients receiving 30 to 40μg/kg/day, and the power and volume of well preserved muscles was increased [24]. In the current study efficacy was demonstrated for a low dose of clenbuterol, which supports the feasibility of translation to clinical use in Pompe disease. Finally, oral albuterol was previously administered to 5 patients with late-onset Pompe disease, resulting in improvement of a functional score in absence of side effects [25]. One of these subjects experienced complications with injected albuterol, and tolerated subsequent treatment with oral albuterol. Clearly this use of albuterol requires evaluation of safety and efficacy, but encouraging efficacy has currently been demonstrated for the equivalent dose of albuterol in combination with ERT in mice with Pompe disease.

The blood brain barrier remains a significant obstacle to therapy in lysosomal storage disorders, either in the form of ERT or gene therapy. It has been hypothesized that low phosphorylation of lysosomal enzymes and low expression of the CI-MPR prevented the uptake of lysosomal enzymes and biochemical correction of the brain in lysosomal storage disorders, perhaps especially in Pompe disease as reflected by very high dosage requirements [26]. Several strategies have been developed to attempt to surpass the obstacle of the blood brain barrier, including high dosages [27], modification of the enzyme [28], neonatal administration [29–31], permeabilizing with mannitol [32], and intrathecal administration, and these strategies have yielded mixed success. Indeed, some disorders seem to respond to peripheral administration or expression of the therapeutic enzyme and to be corrected without direct intrathecal administration of the therapeutic agent [27; 31]. None of these experiments have successfully manipulated CI-MPR to achieve efficacy, in contrast with the administration of clenbuteral that has now increased CI-MPR levels in the brain and enhanced the biochemical correction of the brain in Pompe disease. These data support the possibility that clenbuterol will be a useful adjunctive therapy for other lysosomal storage disorders such as mucopolysaccharidoses that feature severe brain involvement [33]. Enhanced central nervous system uptake of rhGAA in the current experiments correlated with increased CI-MPR expression, which has been postulated as a mechanism for circumventing the blood-brain barrier during ERT in lysosomal storage disorders [26]. Recently an in vitro model of the blood-brain barrier revealed that arylsulfatase A uptake across the barrier was partially dependent upon CI-MPR, further validating the role of CI-MPR in the entry of lysosomal enzymes into the central nervous system [34].

The current experiments demonstrated that the efficacy of GAA replacement therapy was enhanced by β2 agonist administration. These adjunctive therapies might correct brain abnormalities in lysosomal storage disorders non-invasively, by the systemic administration of a drug and ERT. Furthermore, increasing CI-MPR expression could reduce the dosage requirements for ERT or in future trials of gene therapy. Overall, the availability of improved treatments for Pompe disease and other lysosomal storage disorders will improve the benefits and reduce the costs of therapies for these diseases. These preclinical data predict that the response to ERT in Pompe disease might be improved by treatment with clenbuterol or a similarly active β2 agonist drug.

Highlights.

Adjunctive therapy with β2-agonists enhanced enzyme replacement therapy in Pompe disease

  • The efficacy of a lower dose for clenbuterol, and the efficacy of a second β2-agonist in albuterol

  • The enhanced correction of the brain following β2-agonist treatment

  • The CI-MPR dependence of β2-agonist enhancement.

Acknowledgments

This work was supported by NIH Grant R01 HL081122 from the National Heart, Lung, and Blood Institute. GAA-KO mice were provided courtesy of Dr. Nina Raben at the National Institutes of Health (Bethesda, MD). Genzyme Corporation provided rhGAA. We thank Andrew Bird for technical support.

Footnotes

Conflict of interest:

PSK and DDK have received research/grant support from Genzyme Corporation in the past. BT is currently employed by Genzyme Corporation.

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