Texas Children's Case Report Suggests Novel Therapy for GSD1a-Associated Hypertriglyceridemia

A team of physician-scientists at Texas Children’s Hospital and Baylor College of Medicine has reported what may be a promising new treatment strategy for patients living with glycogen storage disease type 1a (GSD1a), a rare inherited disorder that can cause dangerously high triglyceride levels and recurrent pancreatitis. The findings were recently published in JACC: Case Reports.

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Led by senior author Justin P. Zachariah, MD, MPH, Co-chair of Research Operations for the Texas Children's Hospital Heart Center and Associate Professor of Pediatrics at Baylor College of Medicine, the team describes the first reported use of apolipoprotein C-III antisense oligonucleotide (ApoC-III ASO) therapy in a patient with GSD1a-associated hypertriglyceridemia. 

Addressing GSD1a Complications

GSD1a is a rare genetic disorder in which a critical enzyme needed for the control of blood sugar levels is deficient.  This causes impaired glycogen breakdown and gluconeogenesis, leading to the development of severe metabolic pathologies in patients including severe hypertriglyceridemia, hypoglycemia, recurrent pancreatitis, and other complications. Importantly, hypertriglyceridemia is difficult to control with conventional therapies and despite strict diets.

The investigators explored whether olezarsen, an ApoC-III antisense oligonucleotide currently approved for the treatment of severe hypertriglyceridemia in familial chylomicronemia syndrome, might also benefit patients with GSD1a. ApoC-III is a protein involved in triglyceride metabolism, and inhibiting its activity can enhance the body's ability to clear triglycerides from the bloodstream. 

Remarkable Improvement in a Patient with Severe Disease

The GSD1a patient in this report had experienced more than 30 hospitalizations related to his disease, including multiple episodes of pancreatitis. His triglyceride levels remained extremely elevated with conventional treatment, however, after just a few weeks on olezarsen therapy, his triglycerides dropped more than 65% and the improvement persisted through subsequent follow-up, and no additional episodes of pancreatitis reported during the observation period. This is the first reported use of ApoC-III antisense therapy in GSD1a-associated hypertriglyceridemia.

Looking Ahead

Further investigation is still needed to determine the long-term safety and efficacy of this approach, but the findings suggest that ApoC-III ASO therapy may offer a new option for patients with severe GSD1a-associated hypertriglyceridemia that has not responded adequately to conventional treatments.  ApoC-III ASO therapy may be potentially transformative for GSD1a pediatric patients, who can face life-threatening pancreatitis related to severely high triglyceride levels. 

This case highlights the importance of physician-scientists who continually seek innovative solutions for patients facing complex medical conditions and underscores Texas Children's commitment to advancing patient care through research and discovering new therapeutic opportunities for patients with challenging and often underserved conditions. 

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Co-authors Joseph Burns and V. Reid Sutton are also members of Texas Children's Hospital and Baylor College of Medicine. 

This work was supported in part by the National Heart, Lunch and Blood Institute (JZ).