Long-term neurologic and cardiac correction by intrathecal gene therapy in Pompe disease

Abstract

Pompe disease is a lysosomal storage disorder caused by acid-α-glucosidase (GAA) deficiency, leading to glycogen storage. The disease manifests as a fatal cardiomyopathy in infantile form. Enzyme replacement therapy (ERT) has recently prolonged the lifespan of these patients, revealing a new natural history. The neurologic phenotype and the persistence of selective muscular weakness in some patients could be attributed to the central nervous system (CNS) storage uncorrected by ERT. GAA-KO 6neo/6neo mice were treated with a single intrathecal administration of adeno-associated recombinant vector (AAV) mediated gene transfer of human GAA at 1 month and their neurologic, neuromuscular, and cardiac function was assessed for 1 year. We demonstrate a significant functional neurologic correction in treated animals from 4 months onward, a neuromuscular improvement from 9 months onward, and a correction of the hypertrophic cardiomyopathy at 12 months. The regions most affected by the disease i.e. the brainstem, spinal cord, and the left cardiac ventricular wall all show enzymatic, biochemical and histological correction. Muscle glycogen storage is not affected by the treatment, thus suggesting that the restoration of muscle functionality is directly related to the CNS correction. This unprecedented global and long-term CNS and cardiac cure offer new perspectives for the management of patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0464-2) contains supplementary material, which is available to authorized users.

Assessment of adeno-associated virus gene therapies efficacy on acid alpha-glucosidase restoration and glycogen storage correction in cardiac muscle of Pompe disease mice using synchrotron infrared and ultraviolet microspectroscopies

“…These results are consistent with those obtained using biochemical glycogen assay performed on AAV9-and AAV10-treated Pompe cardiac muscles. 26 Furthermore, the heterogeneity observed inside the AAV9-treated Pompe mice cluster was in agreement with the variability of the glycogen storage correction previously described in AAV9-treated mice cardiac muscle from GAA and glycogen assay. 26 The results are in accordance with previous studies published by Hordeaux et al 26 that demonstrated a better efficiency of the AAV9 vector for the correction of cardiac muscle in Pompe disease by using conventional approaches as glycogen biochemical assay, GAA enzymatic activity measurements and histological investigations.…”

“…These biomarkers are routinely analysed by performing biochemical assays and histopathological investigations consisting of glycogen PAS staining and GAA immunohistochemistry on tissue sections. 15,26,[55][56][57] Glycogen PAS staining is based on the principle of periodic acidinduced oxidative cleavage of carbon-to-carbon bounds in 1,2-glycols to form dialdehydes reacting with fuchsinsulphurous acid, which in turn combines with the basic pararosaline, yielding a magenta-like stain. 58 PAS staining could be used to quantify glycogen in tissue sections but the thickness of the sections has to remain constant to ensure the validity of the comparison of glycogen content between sections.…”

“…24,25 We also demonstrated that intra-CSF administration of an AAV9 and AAVrh10 expressing hGAA therapeutic transgene in GAA-KO 6 neo /6 neo Pompe mice, allowed significant decrease of glycogen storage into the brain, spinal cord and cardiac muscle, at the histological and molecular levels, with higher efficiency using serotype 9. 26 Significant functional neurologic correction was obtained starting at four months and hypertrophic cardiomyopathy correction was observed at twelve months in AAV9-treated animals. Classical methods for histologic investigation of glycogen storage are based on periodic acid Schiff (PAS) staining in Pompe disease patients as well as in animal models.…”

Improvement in Cardiac Function With Enzyme Replacement Therapy in a Patient With Infantile-Onset Pompe Disease

“…6 New trials in Pompe disease based on gene therapy are currently ongoing. 12 However, treatment of severe cardiac disease remains quite challenging. [13][14][15] CONCLUSION Typically, patients with infantile-onset Pompe disease and severe hypertrophic cardiomyopathy are not as responsive to enzyme replacement therapy as patients with mild or no hypertrophic cardiomyopathy.…”

Targeted delivery of acid alpha-glucosidase corrects skeletal muscle phenotypes in Pompe disease mice

“…Abnormalities in the neuromuscular junction have been linked with glycogen deposits in spinal motor neurons in mice 4 , and infantile-onset patients show secondary symptoms indicative of neural involvement 3,29 . Studies normalizing glycogen levels solely in the brain and CNS in PD mice (using AAV gene therapy) have shown correction of some neuromuscular phenotypes even in the absence of improvement in cardiac or skeletal muscle fibers, demonstrating that a full reversion of clinical phenotypes in PD ERT will require multisystem delivery 30,31 . While we and others have seen a trend or partial reduction in CNS glycogen storage (Supplementary Figure S9) 27 , it remains unknown whether this reduction will be clinically significant in PD patients.…”