Physiological Correction of Pompe Disease by Systemic Delivery of Adeno-associated Virus Serotype 1 Vectors

Abstract

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.

Preclinical Toxicology and Biodistribution Studies of Recombinant Adeno-Associated Virus 1 Human Acid α-Glucosidase

“…Studies have demonstrated that rAAV1 vectors transduce skeletal muscle more efficiently than rAAV2 vectors, and do not elicit a humoral immune response to the transgene protein (Chao et al, 2001;Mah et al, 2007). Currently, more than 90 clinical trials have begun using rAAV vectors (Ginn et al, 2013).…”

New insights into therapeutic options for Pompe disease

“…A single systemic delivery of AAV-1 vectors into GAA-KO neonates led to a massive transduction of heart, diaphragm, and liver that persists over 1 yr. Supraphysiological GAA expression led to a reduction of muscle glycogen and to the improvement of cardiac functions (46). The systemic injection of AAV2/8 vectors expressing hGAA into 3 month-old immunodeficient GAA-KO/SCID mice led to massive liver transduction (47,48).…”

Neonatal gene transfer using lentiviral vector for murine Pompe disease: long-term expression and glycogen reduction

“…Mah et al 17 reported physiological improvement of the cardiorespiratory function after neonatal gene transfer of adeno-associated virus (AAV) vector, with the elicitation of anti-hGAA antibody formation that was highest at 11 weeks postinjection followed by a drop after 15 weeks and reduction to background levels by 31 weeks posttreatment. We also attempted to evaluate the physiological cardiac function of mice aged 24 weeks using echocardiography, and found no difference in the echocardiographic parameters between the Gaa À/À -untreated mice and C57BL/6-untreated mice (data not shown).…”

“…9,11 To overcome this hurdle, the use of tissuespecific promoters [12][13][14][15] and the neonatal gene transfer have been described. 16,17 Lentiviral vectors (LV) have been under active consideration for gene therapy for lysosomal storage diseases. 18 Kobayashi et al 19 reported sustained expression of enzymatically active iduronidase in multiple organs in the murine model of mucopolysaccharidosis type I after neonatal intravenous administration of LV.…”