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At least 19 recordsLinked to original sources
PubMed2012

MRI roadmap-guided transendocardial delivery of exon-skipping recombinant adeno-associated virus restores dystrophin expression in a canine model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) cardiomyopathy patients currently have no therapeutic options. We evaluated catheter-based transendocardial delivery of a recombinant adeno-associated virus (rAAV) expressing a small nuclear U7 RNA (U7smOPT) complementary to specific cis-acting splicing signals. Eliminating specific exons restores the open reading frame resulting in translation of truncated dystrophin protein. To test this approach in a clinically relevant DMD model, golden retriever muscular dystrophy (GRMD) dogs received serotype 6 rAAV-U7smOPT via the intracoronary or transendocardial route. Transendocardial injections were administered with an injection-tipped catheter and fluoroscopic guidance using X-ray fused with magnetic resonance imaging (XFM) roadmaps. Three months after treatment, tissues were analyzed for DNA, RNA, dystrophin protein, and histology. Whereas intracoronary delivery did not result in effective transduction, transendocardial injections, XFM guidance, enabled 30&#xb1;10 non-overlapping injections per animal. Vector DNA was detectable in all samples tested and ranged from <1 to >3000 vector genome copies per cell. RNA analysis, western blot analysis, and immunohistology demonstrated extensive expression of skipped RNA and dystrophin protein in the treated myocardium. Left ventricular function remained unchanged over a 3-month follow-up. These results demonstrated that effective transendocardial delivery of rAAV-U7smOPT was achieved using XFM. This approach restores an open reading frame for dystrophin in affected dogs and has potential clinical utility.

Animals↗
PubMed2023

Assessment of systemic AAV-microdystrophin gene therapy in the GRMD model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by the absence of dystrophin, a membrane-stabilizing protein encoded by the DMD gene. Although mouse models of DMD provide insight into the potential of a corrective therapy, data from genetically homologous large animals, such as the dystrophin-deficient golden retriever muscular dystrophy (GRMD) model, may more readily translate to humans. To evaluate the clinical translatability of an adeno-associated virus serotype 9 vector (AAV9)-microdystrophin (&#x3bc;Dys5) construct, we performed a blinded, placebo-controlled study in which 12 GRMD dogs were divided among four dose groups [control, 1 &#xd7; 1013 vector genomes per kilogram (vg/kg), 1 &#xd7; 1014 vg/kg, and 2 &#xd7; 1014 vg/kg; n = 3 each], treated intravenously at 3 months of age with a canine codon-optimized microdystrophin construct, rAAV9-CK8e-c-&#x3bc;Dys5, and followed for 90 days after dosing. All dogs received prednisone (1 milligram/kilogram) for a total of 5 weeks from day -7 through day 28. We observed dose-dependent increases in tissue vector genome copy numbers; &#x3bc;Dys5 protein in multiple appendicular muscles, the diaphragm, and heart; limb and respiratory muscle functional improvement; and reduction of histopathologic lesions. As expected, given that a truncated dystrophin protein was generated, phenotypic test results and histopathologic lesions did not fully normalize. All administrations were well tolerated, and adverse events were not seen. These data suggest that systemically administered AAV-microdystrophin may be dosed safely and could provide therapeutic benefit for patients with DMD.

Animals↗
PubMed1976

Erythrocyte spectrin peak II phosphorylation in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a rapidly progressive crippling disease of young boys that is inherited as an X-linked recessive trait. Previous studies have demonstrated the usefulness of erythrocyte studies in exploring membrane abnormalities in inheritied muscular dystrophy. Erythrocyte spectrin peak II protein (m.w. equivalent to 220,000) was more highly phosphorylated under initial rate conditions in DMD than in controls. The extent of peak II phosphorylation was greater in DMD erythrocytes and a Na+ stimulated peak II phosphorylation effect (Avruch and Fairbanks 1974) was not found to account for the differences between DMD and controls. The phosphorylated state of spectrin proteins in the membrane was evaluated and no differences in DMD could be measured. The maximal transfer of phosphate from differences in DMD could be measured. The maximal transfer of phosphate from [gamma-32P]ATP to spectrin peak II accounts for approximately 5-10% of the total phosphate content of spectrin.

Adenosine Triphosphate↗
PubMed1975

Newborn screening for Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) occurs in about 1 of 3,000 to 4,000 boys. Laboratory evidence of the disease, notably elevated creatinephosphokinase (CPK), is present already in the newborn infant. Unspecific CPK elevation occurs in the newborn as well, yet disappears shortly thereafter, while in DMD patients the CPK remains high throughout infancy. A new method to reliably determine CPK in a drop of dried blood is described. The method fulfills the criteria given for a suitable screening method in the newborn infant. Although DMD is an incurable disease, early diagnosis has benefits. The latter include early beginning of supportive treatment and particularly recognition of heterozygous carriers of the mutant gene before other affected children are born in a stricken family. It is proposed to adopt the method as a new screening procedure for male newborn infants.

Adenosine Diphosphate↗
PubMed1979

Effect on maximal strength of submaximal exercise in Duchenne muscular dystrophy.

Four Duchenne muscular dystrophy patients, with quadriceps of at least antigravity strength, exercised one quadriceps submaximally 4 or 5 days per week for six months. The exercise was done under supervision and consisted of extending one knee from 90 degrees to full extension using the Cybex isokinetic exerciser. The other side was not exercised at all. The two sides were tested for maximal isokinetic strength monthly for twelve months and at 18 and 24 months after the beginning of the study. On the average, the exercised leg had a greater maximal torque both during and after the exercise period until the torques on both sides decreased to zero. The results indicate that submaximal exercise has no negative effect and may be of limited value in increasing strength in Duchenne muscular dystrophy.

Child, Preschool↗
PubMed2023

Single-swap editing for the correction of common Duchenne muscular dystrophy mutations.

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disease of progressive muscle weakness and wasting caused by the absence of dystrophin protein. Current gene therapy approaches using antisense oligonucleotides require lifelong dosing and have limited efficacy in restoring dystrophin production. A gene editing approach could permanently correct the genome and restore dystrophin protein expression. Here, we describe single-swap editing, in which an adenine base editor edits a single base pair at a splice donor site or splice acceptor site to enable exon skipping or reframing. In human induced pluripotent stem cell-derived cardiomyocytes, we demonstrate that single-swap editing can enable beneficial exon skipping or reframing for the three most therapeutically relevant exons-DMD exons 45, 51, and 53-which could be beneficial for 30% of all DMD patients. Furthermore, an adeno-associated virus delivery method for base editing components can efficiently restore dystrophin production locally and systemically in skeletal and cardiac muscles of a DMD mouse model containing a deletion of Dmd exon 44. Our studies demonstrate single-swap editing as a potential gene editing therapy for common DMD mutations.

AAV↗
PubMed1978

Biochemical relationships between muscle and erythrocyte membrane. Interpretations with respect to Duchenne muscular dystrophy.

Whether Duchenne muscular dystrophy (DMD) is a disease of primary myogenic, secondary neuropathic, vascular or membrane etiology is the subject of some debate. Using the erythrocyte membrane as a biopsy tissue we present biochemical data that support the possibility of a defect in myosin as the genetic defect in DMD. Peptide analysis of hydrolyzed erythrocyte spectrin supports previous data demonstrating an alteration in DMD spectrin. The biochemical and biophysical similarities between spectrin and myosin can be tested with available technology. The hypothesis that a defect in myosin may be responsible for DMD is attractive because it is testable.

Erythrocyte Membrane↗
PubMed2015

Perspective on Adeno-Associated Virus Capsid Modification for Duchenne Muscular Dystrophy Gene Therapy.

Duchenne muscular dystrophy (DMD) is a X-linked, progressive childhood myopathy caused by mutations in the dystrophin gene, one of the largest genes in the genome. It is characterized by skeletal and cardiac muscle degeneration and dysfunction leading to cardiac and/or respiratory failure. Adeno-associated virus (AAV) is a highly promising gene therapy vector. AAV gene therapy has resulted in unprecedented clinical success for treating several inherited diseases. However, AAV gene therapy for DMD remains a significant challenge. Hurdles for AAV-mediated DMD gene therapy include the difficulty to package the full-length dystrophin coding sequence in an AAV vector, the necessity for whole-body gene delivery, the immune response to dystrophin and AAV capsid, and the species-specific barriers to translate from animal models to human patients. Capsid engineering aims at improving viral vector properties by rational design and/or forced evolution. In this review, we discuss how to use the state-of-the-art AAV capsid engineering technologies to overcome hurdles in AAV-based DMD gene therapy.

Animals↗
PubMed1978

Sequence of cardiac changes in Duchenne muscular dystrophy.

Boys with Duchenne muscular dystrophy (DMD) rarely have clinical evidence of myocardial dysfunction during life. Nevertheless, congestive heart failure is a frequent terminal event and autopsy invariably shows dystrophic myocardial involvement. Little is known regarding the progression of heart functional abnormalities in boys with DMD from birth to death. Therefore we have examined the hearts of 18 DMD boys aged 4 to 15 years with the following non-invasive methods: cardiovascular physical examination, electrocardiography, chest x-ray, serum enzymes, and echocardiography. Control subjects were 25 normal boys matched to their DMD counterparts by age and by body surface area. The dystrophic patients were divided into early (N = 9) and late (N = 9) DMD according to manual muscle testing of skeletal muscles. In early DMD, six of 23 cardiac indices differed from control boys; in the late stage, an additional five indices became abnormal. Early DMD was characterized by these abnormalities: tachycardia, large ECG R/S ratio in V1, augmented q wave voltages in Leads I, II, and V5 of the ECG, diminished contractile excursion of the left venticular posterior wall (LVPW) and interventricular septum, and decreased rate of relaxation of the LVPW. In late DMD additional cardiac abnormalities appeared: enlarged heart volume by x-ray, reduced cardiac ejection fraction, diminished change in left ventricular diameter from diastole to systole, reduced maximal systolic endocardial velocity, and decreased rate of circumferential fiber shortening as detected in the echocardiogram. Most of the cardiac abnormalities were revealed only by echocardiography, which is thus shown to be a sensitive method for monitoring the progression of cardiac dystrophy during the life span of the DMD child.

Adolescent↗
PubMed1977

Walter J. Zeiter Lecture: pathokinesiology of Duchenne muscular dystrophy: implications for management.

Management of Duchenne muscular dystrophy from the beginning of Duchenne's description has always been fragmentary. Even today the operations recommended, bracing suggested and exercise regimens prescribed are not coherent with the pathokinesiologic features of the condition. A review of the course of Duchenne muscular dystrophy in 90 patients over a 16-year period clarified the pathokinesiology of this predictable progressive condition.

Child↗
PubMed1977

Lactate dehydrogenase isoenzyme in detecting carriers of Duchenne muscular dystrophy.

Thirty mothers of patients with Duchenne muscular dystrophy were studied with serum enzyme tests, including serum glutamic-oxaloacetic transminase, creatine kinase, and lactate dehydrogenase isoenzymes. In addition, females from the mothers' pedigrees were studied. Lactate dehydrogenase isoenzyme 5 determinations were as senitive an indicator of carrier status as creatine kinase and also identified several mothers who had normal dehydrogenase isoenzyme 5 determinations, as well as extensive pedigree testing, identified 28 to 30 mothers as probable heterozygotes. These data independently support the suggestion that cases of Duchenne muscular dystrophy as a result of spontaneous mutation are more uncommon than currently accepted.

Adult↗
PubMed1978

Electron spin resonance studies of erythrocytes from patients with Duchenne muscular dystrophy.

The membrane organization of the erythrocytes from patients with Duchenne muscular dystrophy was studied by means of electron spin resonance. The fluidity of the membrane near the polar region of Duchenne muscular dystrophy erythrocytes was similar to that of normal erythrocytes. The membrane environment in the nonpolar region, however, was quite different from that of normal erythrocytes, judged by the spectra with 2-(14-carboxytetradecyl) - 2 - ethyl - 4,4 - dimethyl - 3 - oxazolidinyloxyl as probe. The temperature dependence of the ratio of the line height of central field to that at the low field showed two inflection points in normal erythrocytes at pH 7.4 (13.5 degrees -16.5 degrees and 37.5 degrees -40.5 degrees C, respectively) but the inflection point in the lower temperature range was not detected in Duchenne muscular dystrophy erythrocytes. When pH was varied, an abrupt decrease in the ratio was observed at pH 5.9-5.6 in normal erythrocytes whereas there was a gradual decrease over the range of pH from 6.6 to 5.0 in Duchenne muscular dystrophy erythrocytes. The rate of reduction of the radical 2-(3-carboxypropyl)-4,4-dimethyl-2-tridecyl-3-oxazolidinyloxyl by ascorbate in normal erythrocytes was faster than that in Duchenne muscular dystrophy erythrocytes. Treatment of both erythrocytes with phloretin markedly reduced the rate of reduction by ascorbate and eliminated the difference in the two types of erythrocyte. These results indicate that in Duchenne muscular dystrophy the erythrocyte membrane is involved as well as the muscle cell.

Adolescent↗
PubMed2026

Duchenne muscular dystrophy: from gene to gene-ius therapies.

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder caused by mutations in the dystrophin gene that result in the absence of functional dystrophin, leading to progressive muscle degeneration, loss of ambulation, respiratory failure, cardiomyopathy, and premature mortality. Despite advances in multidisciplinary supportive care, DMD remains an incurable disease associated with substantial physical, psychosocial, and economic burdens. The monogenic nature of DMD and its well-defined molecular pathogenesis have made it a prime target for the development of precision therapies aimed at restoring dystrophin expression or modifying disease progression. This review provides an overview of the genetic and molecular mechanisms underlying DMD, summarizes its clinical manifestations and natural history, and discusses current standards of care. It further examines recent advances in disease-modifying therapeutic strategies, including exon-skipping antisense oligonucleotides, nonsense mutation readthrough agents, adeno-associated virus (AAV)-mediated micro-dystrophin gene replacement, and emerging genome-editing technologies such as CRISPR/Cas9. The review also highlights the limitations of existing treatments, including mutation specificity, variable efficacy, immune-related challenges, and uncertainties regarding long-term durability and safety. Finally, it considers future directions in therapeutic development, emphasizing the need for combination approaches, improved delivery systems, and next-generation gene-editing platforms to achieve more effective and lasting clinical outcomes. Collectively, these advances represent a paradigm shift in DMD management and offer renewed hope for improving survival and quality of life for affected individuals.

Humans↗
PubMed1977

Pedigree testing in Duchenne muscular dystrophy.

Female relatives of 41 Duchenne muscular dystrophy proband cases were studied with a panel of carrier-detection tests. A total of 277 relatives were tested in order to determine which mothers had affected sons as a result of new mutation. In 39 of 41 pedigrees the data demonstrate that a mutation cannot be postulated; the 2 megative pedigrees were inadequately tested. Our data suggest that all mothers of affected sons should be considered genetic carriers (heterozygotes) until proved otherwise. Our findings also raise questions concerning what mechanisms skew the indirect statistical estimates of mutation that are in common use.

Adolescent↗
PubMed1979

Detection and genetic counselling of subclinical and carrier states in Duchenne muscular dystrophy.

23 potential carriers of Duchenne muscular dystrophy (DMD) and 20 of their apparently healthy brothers were studied for evidence of any subclinical form of the disease. The results of the study confirmed that it was possible to confirm the diagnosis of a 'high genetic risk' carrier by integrating the results of clinical studies, estimation of basal serum CPK, steroid-CPK test, EMG and ECG observations. Similarly, the subclinical state of DMD could also be detected with certainty in 10% of the brothers of DMD carriers. The results may be applied for genetic counselling to bring down the incidence of the disease in the community.

Adolescent↗
PubMed1977

Stabilization of the collapsing spine in duchenne muscular dystrophy.

Of 41 patients with Duchenne muscular dystrophy, no ambulatory patient had scoliosis greater than 19 degrees. Non-ambulatory patients were prophylactically placed in body jackets, which kept the spine flexible and provided adequate support for sitting in the majority of patients. Ten patients had posterior spine fusion for progressive spinal collapse. The procedure was extensive with significant blood loss but boney fusion was achieved in every case. Pulmonary complications were minimized by performing preoperative tracheostomy on all patients who had vital capacities less than 40% and or non-functional coughs. Spinal fusion permitted long-term sitting stability despite the progression of the disease.

Adolescent↗
PubMed1978

Chemical compositional studies of erythrocyte membranes in Duchenne muscular dystrophy.

Erythrocytes from patients with Duchenne muscular dystrophy (DMD) are known to possess a number of structural and functional abnormalities, including an increased osmotic fragility and potassium permeability, a decreased deformability and altered electrophoretic behaviour. To explore the possible chemical basis of these changes, the compositional properties of erythrocyte membranes from patients with DMD and a number of suspected carriers for this disorder have been investigated. Quantitative analyses of membrane cholesterol, sialic acid and major phospholipid classes were normal in both groups of individuals and no alterations in the arrangement of membrane amino and sulfhydryl groups could be detected. It is suggested that increased levels of cellular calcium, possibly occurring as the result of a defect in active calcium extrusion, could account for the structural and functional abnormalities of erythrocytes in DMD.

Adolescent↗