Low dose ampakine CX717 increases ventilation in a rat model of Pompe Disease (2023)

Pompe disease (PD) is an autosomal recessive metabolic disorder caused by mutations in the enzyme acid-α-glucosidase (GAA) gene. Loss of GAA function causes pathologic accumulation of cellular glycogen. Both early- and late-onset PD are characterized by respiratory dysfunction often leading to ventilator-dependence. Our group has recently designed a rat model of PD using Zinc Finger Nuclease (ZFN) technology that mimics the clinical phenotype of early onset PD. ZFN pompe rats exhibit neuromuscular respiratory pathology along with reduced tidal volume and respiratory rate by 8 months. Ampakines are positive allosteric modulators of AMPA receptors that can stimulate breathing following spinal cord injury or opioid induced respiratory depression. We previously reported that ampakine CX717 delivered at 15 and 30 mg/kg could stimulate breathing in a mouse model of PD. Here we aimed to determine if a lower dose (5 mg/kg) could effectively stimulate breathing in the adult rat ZFN PD model. Ampakine (CX717; 5 and 15mg/kg) or vehicle (HPCD) treatment were administered in 8 mo ZFN PD male (n=9) and female (n=9) rats. Ventilation was measured using a whole-body plethysmograph. A tail vein catheter was externalized through a dedicated port in the plethysmograph chamber to enable infusion of ampakine or vehicle during the experiment. The 5mg/kg and 15mg/kg dose of CX717 caused an acute increase in tidal volume (17±6%, 17±4% respectively; p=0.04), respiratory rate (146±17%, 137 ± 15% respectively; p&lt;0.001), and minute ventilation (184±23%, 181±24% respectively; p&lt;0.001), whereas infusion of the HPCD vehicle had a relatively smaller impact on respiratory rate (+40 ± 14%) and minute ventilation (+36 ± 11%). Further, there was no effect of HPCD infusion on tidal volume at any time during or post infusion. Additionally, the 5mg/kg but not the 15 mg/kg CX717 infusion produced a sustained increase in minute ventilation (60 ± 20 % baseline after 15 min, p=0.0029). During a hypoxic (10.5% O 2 , 79% N 2 ) respiratory challenge, rats treated with the low dose of CX717 had a greater increase in tidal volume (38 ± 5%; p=0.0079), respiratory rate (107 ± 11%; p&lt;0.001) and minute ventilation (188 ± 22%; p&lt;0.001) as compared to the 15mg/kg (19 ± 3%, 59 ± 8%, 91 ± 12% respectively) or HPCD (22 ± 3%, 39 ± 10% and 69 ± 10% respectively) groups. The same was true during the maximum hypoxic-hypercapnic (10.5% O 2 , 7% CO 2 balanced N 2 ) challenge: rats treated with the low dose CX717 had a higher increase in respiratory rate (110 ± 12%; p&lt;0.001) and minute ventilation (511 ± 57%; p&lt;0.001) as compared to the 15mg/kg (80 ± 6% and 382 ± 33%) or HPCD (27 ± 9% and 246 ± 29%) groups. We conclude that low dose (5 mg/kg) ampakine treatment can increase ventilation in male and female rats with PD. This may provide a pharmacological strategy to treat respiratory insufficiency in PD. Funding: R01 HL139708 (DDF), 2R01HD052682-11A1 (DDF, BJB), Craig Nielsen Foundation SCIRTS Fellowship (SR). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.