Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycogen storage disease type II (GSDII) is caused by a lack of functional lysosomal acid alpha-glucosidase (GAA). Affected individuals store glycogen in lysosomes beginning during gestation, ultimately resulting in fatal hypertrophic cardiomyopathy and respiratory failure. We have assessed the utility of recombinant adeno-associated virus (rAAV) vectors to restore GAA activity in vivo in a mouse model of GSDII (Gaa(-/-)). A single systemic administration of a rAAV serotype 1 (rAAV1) vector to neonate animals resulted in restored cardiac GAA activity to 6.4 times the normal level (mean=641+/-190% of normal (Gaa(+/+)) levels with concomitant glycogen clearance) at 11 months postinjection. Greater than 20% of normal levels of GAA activity were also observed in the diaphragm and quadriceps muscles. Furthermore, functional correction of the soleus skeletal muscle was also observed compared to age-matched untreated Gaa(-/-) control animals. These results demonstrate that rAAV1 vectors can mediate sustained therapeutic levels of correction of both skeletal and cardiac muscles in a model of fatal cardiomyopathy and muscular dystrophy.
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PMID:Sustained correction of glycogen storage disease type II using adeno-associated virus serotype 1 vectors. 1592 Apr 63

Glycogen storage disease type II (GSD-II) patients manifest symptoms of muscular dystrophy secondary to abnormal glycogen storage in cardiac and skeletal muscles. For GSD-II, we hypothesized that a fully deleted adenovirus (FDAd) vector expressing hGAA via nonviral regulatory elements (PEPCK promoter/ApoE enhancer) would facilitate long-term efficacy and decrease propensity to generate anti-hGAA antibody responses against hepatically secreted hGAA. Intravenous delivery of FDAdhGAA into GAA-tolerant or nontolerant GAA-KO mice resulted in long-term hepatic secretion of hGAA. Specifically, nontolerant mice achieved complete reversal of cardiac glycogen storage and near-complete skeletal glycogen correction for at least 180 days and tolerant mice for minimally 300 days coupled with the preservation of muscle strength. Anti-hGAA antibody levels in both mouse strains were significantly less relative to those previously generated by CMV-driven hGAA expression in nontolerant GAA-KO mice. However, plasma GAA levels decreased in nontolerant GAA-KO mice despite long-term intrahepatic GAA expression from the persistent vector. This intriguing result is discussed in light of other examples of "tolerance" induction by gene-transfer-based approaches.
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PMID:Fully deleted adenovirus persistently expressing GAA accomplishes long-term skeletal muscle glycogen correction in tolerant and nontolerant GSD-II mice. 1616 80

Glycogen storage disease type II (GSD-II; Pompe disease; MIM 232300) is an inherited muscular dystrophy caused by deficiency in the activity of the lysosomal enzyme acid alpha-glucosidase (GAA). We hypothesized that chimeric GAA containing an alternative signal peptide could increase the secretion of GAA from transduced cells and enhance the receptor-mediated uptake of GAA in striated muscle. The relative secretion of chimeric GAA from transfected 293 cells increased up to 26-fold. Receptor-mediated uptake of secreted, chimeric GAA corrected cultured GSD-II patient cells. High-level hGAA was sustained in the plasma of GSD-II mice for 24 weeks following administration of an AAV2/8 vector encoding chimeric GAA; furthermore, GAA activity was increased and glycogen content was significantly reduced in striated muscle and in the brain. Administration of only 1 x 10(10) vector particles increased GAA activity in the heart and diaphragm for >18 weeks, whereas 3 x 10(10) vector particles increased GAA activity and reduced glycogen content in the heart, diaphragm, and quadriceps. Furthermore, an AAV2/2 vector encoding chimeric GAA produced secreted hGAA for >12 weeks in the majority of treated GSD-II mice. Thus, chimeric, highly secreted GAA enhanced the efficacy of AAV vector-mediated gene therapy in GSD-II mice.
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PMID:Enhanced efficacy of an AAV vector encoding chimeric, highly secreted acid alpha-glucosidase in glycogen storage disease type II. 1698 11

Pompe disease is caused by a lack of functional lysosomal acid alpha-glucosidase (GAA) and can ultimately lead to fatal hypertrophic cardiomyopathy and respiratory insufficiency. Previously, we demonstrated the ability of recombinant adeno-associated virus serotype 1 (rAAV2/1) vector to restore the therapeutic levels of cardiac and diaphragmatic GAA enzymatic activity in vivo in a mouse model of Pompe disease. We have further characterized cardiac and respiratory function in rAAV2/1-treated animals 1 year post-treatment. Similar to the patient population, electrocardiogram measurements (P-R interval) are significantly shortened in the Pompe mouse model. In rAAV2/1-treated mice, we show a significant improvement in cardiac conductance with prolonged P-R intervals of 39.34+/-1.6 ms, as compared to untreated controls (35.58+/-0.57 ms) (P</=0.05). In addition, we note a significant decrease in cardiac left ventricular mass from 181.99+/-10.70 mg in untreated controls to 141.97+/-19.15 mg in the rAAV2/1-treated mice. Furthermore, the mice displayed an increased diaphragmatic contractile force of approximately 90% of wild-type peak forces with corresponding improved ventilation (particularly in frequency, minute ventilation, and peak inspiratory flow). These results demonstrate that in addition to biochemical and histological correction, rAAV2/1 vectors can mediate sustained physiological correction of both cardiac and respiratory function in a model of fatal cardiomyopathy and muscular dystrophy.
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PMID:Physiological correction of Pompe disease by systemic delivery of adeno-associated virus serotype 1 vectors. 1724 50

Pompe disease is a severe form of muscular dystrophy due to glycogen accumulation in all tissues, especially striated muscle. Disease severity is directly related to the deficiency of acid alpha-glucosidase (GAA), which degrades glycogen in the lysosome. Respiratory dysfunction is a hallmark of the disease, muscle weakness has been viewed as the underlying cause, and the possibility of an associated neural contribution has not been evaluated previously. Therefore, we examined behavioral and neurophysiological aspects of breathing in 2 animal models of Pompe disease--the Gaa(-/-) mouse and a transgenic line (MTP) expressing GAA only in skeletal muscle, as well as a detailed analysis of the CNS in a Pompe disease patient. Glycogen content was elevated in the Gaa(-/-) mouse cervical spinal cord. Retrograde labeling of phrenic motoneurons showed significantly greater soma size in Gaa(-/-) mice vs. isogenic controls, and glycogen was observed in Gaa(-/-) phrenic motoneurons. Ventilation, assessed via plethysmography, was attenuated during quiet breathing and hypercapnic challenge in Gaa(-/-) mice (6 to >21 months of age) vs. controls. We confirmed that MTP mice had normal diaphragmatic contractile properties; however, MTP mice had ventilation similar to the Gaa(-/-) mice during quiet breathing. Neurophysiological recordings indicated that efferent phrenic nerve inspiratory burst amplitudes were substantially lower in Gaa(-/-) and MTP mice vs. controls. In human samples, we demonstrated similar pathology in the cervical spinal cord and greater accumulation of glycogen in spinal cord compared with brain. We conclude that neural output to the diaphragm is deficient in Gaa(-/-) mice, and therapies targeting muscle alone may be ineffective in Pompe disease.
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PMID:Neural deficits contribute to respiratory insufficiency in Pompe disease. 1947 95

Due to the lack of acid alpha-glucosidase (GAA) activity, Pompe mice develop glycogen storage pathology and progressive skeletal muscle dysfunction with age. Applying either gene or enzyme therapy to reconstitute GAA levels in older, symptomatic Pompe mice effectively reduces glycogen storage in skeletal muscle but provides only modest improvements in motor function. As strategies to stimulate muscle hypertrophy, such as by myostatin inhibition, have been shown to improve muscle pathology and strength in mouse models of muscular dystrophy, we sought to determine whether these benefits might be similarly realized in Pompe mice. Administration of a recombinant adeno-associated virus serotype 8 vector encoding follistatin, an inhibitor of myostatin, increased muscle mass and strength but only in Pompe mice that were treated before 10 months of age. Younger Pompe mice showed significant muscle fiber hypertrophy in response to treatment with follistatin, but maximal gains in muscle strength were achieved only when concomitant GAA administration reduced glycogen storage in the affected muscles. Despite increased grip strength, follistatin treatment failed to improve rotarod performance. These findings highlight the importance of treating Pompe skeletal muscle before pathology becomes irreversible, and suggest that adjunctive therapies may not be effective without first clearing skeletal muscle glycogen storage with GAA.
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PMID:Evaluation of systemic follistatin as an adjuvant to stimulate muscle repair and improve motor function in Pompe mice. 2055 7

Pompe disease is classified into infantile-, childhood- and adult-onset forms based on onset age and the degree of organ involvement. Differing from the infantile-onset form which is characterized by marked organ involvement, the childhood-onset form usually presents with muscle weakness and elevation of serum creatine kinase (CK), mimicking those of progressive muscular dystrophy. We report our successful early diagnosis and initiation of enzyme replacement therapy (ERT) in a young girl with childhood-onset Pompe disease before the development of skeletal muscle symptoms. She was referred to our hospital at the age of 2 years 4 months because of hyperCKemia detected incidentally. She was active and lacked developmental delay and muscle weakness; however, hepatomegaly was noted. The combination of high-density changes in the liver and skeletal muscle on computed tomography (CT) images was suggestive of glycogen storage disorder, especially childhood-onset Pompe disease. Low alpha-glucosidase (GAA) activity on dried blood spots facilitated the diagnostic process, and genetic analysis of GAA allowed a definitive diagnosis, without performing muscle biopsy. We promptly started ERT at the age of 2 years 6 months. After 1 year, she still had not developed any skeletal muscle symptoms, and serum CK level was almost normal. Since the efficacy of ERT is thought to depend on the extent of muscle damage at its commencement, we expect that ERT may have prevented the manifestation of skeletal muscle involvement in this patient.
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PMID:High-density CT of muscle and liver may allow early diagnosis of childhood-onset Pompe disease. 2170 64