Time course of ventilatory failure in a novel rat model of Pompe Disease

Abstract

Pompe disease (PD) is caused by mutations in the gene encoding the enzyme acid-α-glucosidase (GAA). Since GAA acts to degrade lysosomal glycogen, reduced or loss of enzyme activity leads to glycogen accumulation and neuromuscular impairments. Respiratory dysfunction and ventilator-dependence is common in both early- and late-onset PD. Our group has created a rat model of PD using Zinc Finger Nuclease (ZFN) technology. The goal of the current study was to characterize ventilation and metabolism in unrestrained ZFN Pompe rats using whole body plethysmography. Data were collected during a normoxic baseline period, acute exposures to hypoxia (FiO2=10.5%), hypercapnia (FiCO2=7%), and combined hypercapnic-hypoxic challenge intended to produce a maximal ventilatory drive. ZFN Pompe rats and age-matched, wild type (WT) controls were studied at age 3, 6, and 10-11 months to assess ventilation throughout disease progression. Both male and female 3 month old ZFN Pompe rats hyperventilated (greater VE/VCO2) due to greater tidal volume compared to WT rats. However, as the ZFN Pompe rats aged, the ventilatory phenotype changed such that by 10-11 months they showed significant hypoventilation as well as a blunted ability to increase ventilation in response to respiratory challenge relative to WT controls. Histological data from these rats, as well as prior data from the Gaa-/- mouse model of PD, show that respiratory neuromuscular pathology is present at a very young age. Accordingly, the current ventilatory data suggest that animals with PD initially increase breathing in response to the onset of pathology, possibly representing a period of “overcompensation”. However, this is followed by respiratory failure as the respiratory neuromuscular pathology progresses towards disease end-stage.