Long-term complications of glycogen storage disease type Ia in the canine model treated with gene replacement therapy.

BACKGROUND: Glycogen storage disease type Ia (GSD Ia) in dogs closely resembles human GSD Ia. Untreated patients with GSD Ia develop complications associated with glucose-6-phosphatase (G6Pase) deficiency. Survival of human patients on intensive nutritional management has improved; however, long-term complications persist including renal failure, nephrolithiasis, hepatocellular adenomas (HCA), and a high risk for hepatocellular carcinoma (HCC). Affected dogs fail to thrive with dietary therapy alone. Treatment with gene replacement therapy using adeno-associated viral vectors (AAV) expressing G6Pase has greatly prolonged life and prevented hypoglycemia in affected dogs. However, long-term complications have not been described to date. METHODS: Five GSD Ia-affected dogs treated with AAV-G6Pase were evaluated. Dogs were euthanized due to reaching humane endpoints related to liver and/or kidney involvement, at 4 to 8 years of life. Necropsies were performed and tissues were analyzed. RESULTS: Four dogs had liver tumors consistent with HCA and HCC. Three dogs developed renal failure, but all dogs exhibited progressive kidney disease histologically. Urolithiasis was detected in two dogs; uroliths were composed of calcium oxalate and calcium phosphate. One affected and one carrier dog had polycystic ovarian disease. Bone mineral density was not significantly affected. CONCLUSIONS: Here, we show that the canine GSD Ia model demonstrates similar long-term complications as GSD Ia patients in spite of gene replacement therapy. Further development of gene therapy is needed to develop a more effective treatment to prevent long-term complications of GSD Ia.

From theory to therapy: a One Health approach guides current and future acid suppressant use in veterinary medicine.

Acid-suppressant drugs (ASDs) have revolutionized the treatment of acid-related disorders such as gastroesophageal reflux and gastrointestinal ulceration in both human and veterinary species. However, continued advancement in this field is dependent on a shared understanding of both human and veterinary research as well as an appreciation for species similarities and differences. In this Currents in One Health article, we will compare the efficacy of and indications for ASDs in humans and small animals, noting species differences and knowledge gaps when applicable. We will also highlight areas where further research is needed, specifically emphasizing the need for more feline research and a better understanding of which diseases may benefit from gastroprotection. Finally, given the rising overuse of ASDs in both human and veterinary medicine, we will explore the known adverse effects of these drugs in dogs and cats. This article is focused on our current understanding of these drugs in veterinary medicine and their clinical implications. The companion Currents in One Health article by Gould et al, AJVR, October 2024, will explore the future of ASD research and use by evaluating these drugs' pH-independent effects in humans and rodent models.

pH-independent effects of acid suppressants in dogs and cats: a One Health perspective and case for further investigation.

Our understanding of the use of acid-suppressant drugs (ASDs) in companion animals is largely centered around the treatment of acid-related disorders including gastroesophageal reflux and gastrointestinal ulceration. The companion article by Grady et al, JAVMA, October 2024, summarizes our current knowledge of the efficacy of and indications for ASDs for the treatment of acid-related disorders. Far less is understood about both the benefits of and potential for adverse effects of ASDs outside of the parietal cell including those directed toward inflammation and immunomodulation, tumorigenesis, fibrosis, and oxidative stress. In this Currents in One Health article, we summarize the pH-independent properties of ASDs as demonstrated in studies conducted largely in humans and rodents. The objective of this review is to highlight and increase awareness of the pH-independent effects of ASDs to elucidate the need for further veterinary research in this area.

Gastric pH and serum gastrin concentration in age-matched healthy dogs and dogs with chronic kidney disease.

BACKGROUND: Gastric hyperacidity and hypergastrinemia are purported to cause gastric ulceration in dogs with chronic kidney disease (CKD); however, no published studies have evaluated gastric pH with serum gastrin concentrations in dogs with CKD. HYPOTHESIS: To compare mean intragastric pH, mean percent pH distribution, and serum gastrin concentrations in dogs with CKD to age-matched, healthy dogs. We hypothesized there would be no difference in mean gastric pH or serum gastrin between groups. ANIMALS: Thirteen dogs with CKD; 10 aged-matched healthy dogs. METHODS: Prospective, case-control study. Serum chemistry, complete blood count, urinalysis, and serum gastrin concentrations were evaluated in all dogs before radiographic-assisted gastric placement of a pH capsule. Forty-eight-hour continuous gastric pH monitoring was performed in all dogs. Serum gastrin concentration, mean pH, and mean percentage time that gastric pH was strongly acidic (pH <1 and pH <2) were compared between groups using a repeated measures mixed-model ANOVA. RESULTS: No significant differences were observed between groups for any pH measurements, including mean ± SD gastric pH (CKD, 2.37 ± 0.87; healthy, 2.39 ± 0.99; P > .05). Serum gastrin concentrations were not significantly different between groups (median [range]: CKD, 10.5 ng/dL [<10-17.1]; healthy, 10.9 ng/dL [<10-15]; P > .05). CONCLUSIONS AND CLINICAL IMPORTANCE: Our client-owned dogs with CKD did not have lower gastric pH or higher serum gastrin concentrations compared to healthy dogs. Our results suggest that prophylactic gastric acid suppression in dogs with CKD is not warranted unless other clinical indications for use are present.

Daytime and nocturnal activity in treated dogs with idiopathic epilepsy compared to matched unaffected controls.

BACKGROUND: In dogs, antiepileptic drugs (AED) cause lethargy but quantitative data regarding the effects of AED on activity levels are not available, and little is known about how AEDs affect sleep quality. OBJECTIVE: To quantitatively compare activity levels and nocturnal activity in dogs previously diagnosed with idiopathic epilepsy (IE) receiving AEDs compared to age- and breed-matched control dogs. ANIMALS: Sixty-two dogs with IE and 310 control dogs. METHODS: This is a 3-month prospective parallel observational study. An activity monitoring device for dogs was used to measure daily activity levels and sleep scores in all dogs. RESULTS: Dogs with IE treated with AEDs had an 18% average lower baseline activity level compared to control dogs (P = .005; point estimate = 0.82, 95% confidence interval [CI], 0.75-0.90). The combination of phenobarbital and potassium bromide (KBr) was associated with an average 28% decrease in activity in dogs with IE compared to control dogs (P = .03; point estimate = 0.72; CI, 0.62-0.82). Mean sleep scores were not significantly different in dogs with IE receiving AEDs compared to control dogs (P = .43). However, higher dosages of KBr were associated with lower sleep scores (P = .01). CONCLUSIONS: Dogs with IE receiving AEDs have lower activity levels, but no difference in sleep scores, compared to controls. The combination of phenobarbital and KBr had the largest decrease in activity between groups. Higher doses of KBr may affect nocturnal activity in epileptic dogs.

Pathogenesis of Hepatic Tumors following Gene Therapy in Murine and Canine Models of Glycogen Storage Disease.

Glycogen storage disease type Ia (GSD Ia) is caused by mutations in the glucose-6-phosphatase (G6Pase) catalytic subunit gene (G6PC). GSD Ia complications include hepatocellular adenomas (HCA) with a risk for hepatocellular carcinoma (HCC) formation. Genome editing with adeno-associated virus (AAV) vectors containing a zinc-finger nuclease (ZFN) and a G6PC donor transgene was evaluated in adult mice with GSD Ia. Although mouse livers expressed G6Pase, HCA and HCC occurred following AAV vector administration. Interestingly, vector genomes were almost undetectable in the tumors but remained relatively high in adjacent liver (p < 0.01). G6Pase activity was decreased in tumors, in comparison with adjacent liver (p < 0.01). Furthermore, AAV-G6Pase vector-treated dogs with GSD Ia developed HCC with lower G6Pase activity (p < 0.01) in comparison with adjacent liver. AAV integration and tumor marker analysis in mice revealed that tumors arose from the underlying disorder, not from vector administration. Similarly to human GSD Ia-related HCA and HCC, mouse and dog tumors did not express elevated α-fetoprotein. Taken together, these results suggest that AAV-mediated gene therapy not only corrects hepatic G6Pase deficiency, but also has potential to suppress HCA and HCC in the GSD Ia liver.