Simply Stated: Updates in Pompe Disease and Other Glycogen Storage Diseases

Glycogen storage diseases (GSDs) are a group of rare inherited conditions that occur when the body is not able to use or store glycogen properly. People with GSDs may experience frequent low blood sugar (hypoglycemia), muscle weakness, and liver damage. Glycogen is processed by many different enzymes in the body, and defects in some of these individual enzymes can lead to different types of GSD. Most types of GSDs can be managed with treatment. Though estimates vary, GSDs are thought to occur in about one out of every 20,000-43,000 live births.

Cause of GSDs

GSDs are caused by defects in enzymes involved in breaking down or storing glycogen, the stored form of glucose (sugar). When a person eats a meal rich in carbohydrates, their body breaks down the food into glucose, the body’s main source of energy. If there is too much available glucose, enzymes are used to connect these extra glucose molecules together, to create glycogen, and store it in the liver and muscles. When energy is needed during times of extreme physical activity or fasting/starvation, then different enzymes are used to break down the stored glycogen to create glucose again. Mutations in the genes encoding these various enzymes are the cause of GSDs. These mutations can be passed on from parent to child, making GSDs inherited conditions.

Types and symptoms of GSDs

There are at least 19 different types of GSDs, and disease symptoms can vary greatly based on the type and on the person. The onset of a GSD can occur from before birth (in utero) to adulthood. The liver and skeletal muscles (which control voluntary movements) are most affected by GSDs. People with GSDs may experience some of the following characteristic features:

GSDs with liver involvement

·       Low blood sugar (hypoglycemia) – shaking, sweating/chills, dizziness, weakness, fast heart rate, intense hunger, difficulty thinking, anxiety, pale skin, seizures

·       Hepatomegaly (enlarged liver)

GSDs with muscle involvement

·       Muscle pain and cramps

·       Becoming easily tired from physical activity (exercise intolerance)

·       Progressive weakness

·       Slowed growth and poor weight gain in children

·       In some cases:

•  Harmful muscle breakdown (rhabdomyolysis), leading to the presence of muscle proteins in the blood and urine (myoglobinuria)
•  Heart problems like cardiomyopathy and/or conduction defects

The different types of GSDs were traditionally categorized by number according to when their enzyme defect was identified. Researchers know more about some of these diseases than others. A handful of the more commonly recognized GSDs include:

·       GSD type I (Von Gierke disease): Caused by deficiency of the glucose-6-phosphatase enzyme, which leads to glycogen accumulation in the liver.

·       GSD type II (Pompe disease): Caused by deficiency of the acid alpha-glucosidase enzyme, which leads to glycogen buildup in muscles and other tissues.

·       GSD type III (Cori/Forbes disease): Caused by deficiency of the glycogen debranching enzyme, which leads to abnormal glycogen structure in the liver and muscles.

·       GSD type VII (Tarui disease): Caused by deficiency of the phosphofructokinase enzyme, which leads to glycogen accumulation in muscles.

For more information about the types and characteristic symptoms of the GSDs, as well overview of diagnostic and management concerns, an in-depth overview can be found here.

Current management of GSDs

Most current strategies to manage GSDs are designed to alleviate signs and symptoms, but do not fix the underlying cause of disease. To address hypoglycemia and nutritional concerns associated with GSDs, doctors may recommend a modified diet or nutrition/feeding support. Physical therapy may be prescribed to help delay muscle weakness, maintain range of motion, and improve mobility. An individualized plan for cardiac care can help with early detection of heart issues. In severe cases, liver transplantation may be recommended for patients who have GSDs that have progressed to liver failure.

Some GSDs, such as GSD type II (Pompe disease), can be treated with enzyme replacement therapy (ERT), which helps break down accumulated glycogen. Approved treatments for Pompe disease are life-saving, especially in the case of early-onset disease. Several groups are working to improve the efficacy of ERT and to explore its optimal use in late-onset Pompe disease. Approved and emerging therapies for Pompe disease were covered in the 2023 Quest blog post Simply Stated: Research Updates in Pompe Disease, though research advances have been made since that time. In particular, the approval of the advanced ERT option, cipaglucosidase alfa-atga + miglustat, provided a new therapeutic option for adults with late-onset Pompe disease. The potential of ERT to treat other types of GSD is currently being investigated.

Evolving research and treatment landscape

There are many unmet needs for people with GSDs, and researchers are attempting to address these needs through various therapeutic strategies. Both supportive interventions and disease-modifying therapies, including genetic correction strategies, are in the drug development pipeline for GSDs. Some promising therapeutics in development include the following:

Gene therapy

• ACTUS-101 (AskBio/Duke University) – An investigational gene therapy that uses an adeno-associated-virus (AAV)-based vector to replace the alpha-glucosidase (GAA) gene in liver cells. A phase 1/2 clinical trial (ACT-CS101) is assessing the safety and efficacy of this therapeutic approach in patients with Pompe disease. The trial is active, but not recruiting new participants.
• AT845 (Astellas Gene Therapies) – A gene therapy intended to deliver a functional GAA gene to muscle cells. The phase 1/2 trial (FORTIS) aims to assess its safety and efficacy in adults with late-onset Pompe disease. This trial was temporarily on hold due to safety concerns, but is now active and recruiting patients.
• DTX401 (Ultragenyx Pharmaceutical Inc) – An AAV type 8 (AAV8)-based gene therapy to introduce the glucose-6-phosphate gene in people with GSD type Ia (a form of Von Gierke disease). DTX401 is being studied in a phase 3 trial that is active, but not recruiting participants.
• RP-A501 (Rocket Pharmaceuticals Inc.) – An AAV9-based gene therapy to introduce the lysosome-associated membrane protein 2 isoform B (LAMP2B) gene in people with GSD type IIb (Danon disease). RP-A501 is being studied in a phase 2 trial that is active, but not recruiting participants.
• SPK-3006 (Spark Therapeutics) – An investigational gene therapy designed to replace the alpha-glucosidase (GAA) gene in liver cells. A phase 1/2 clinical trial (RESOLUTE) is evaluating its safety and efficacy in adults with late-onset Pompe disease. The study is active but not recruiting new participants.

New therapeutic strategies

• mRNA-3745 (ModernaTX, Inc) – An RNA-based therapy to deliver the glucose-6-phosphate gene message to the liver to treat GSD type Ia. This therapy is being studied in a phase 1/2 trial that is currently enrolling participants.
• BEAM-301 (Beam Therapeutics Inc) – A therapy that uses a gene editing strategy, delivered to the liver using a lipid-nanoparticle (LNP) formula, to correct the underlying genetic defect in GSD type Ia. This therapy is being studied in a phase 1/2 trial that is currently enrolling participants.

These therapies remain in the early stages of development and are not yet widely available. However, they represent promising advancements in the field, with the potential to significantly improve treatment options for GSDs. As clinical trials advance, these innovative approaches could reshape the standard of care, offering more effective, long-term solutions and enhancing the quality of life for individuals affected by GSDs.

To learn more about clinical trial opportunities in GSDs, visit clinicaltrials.gov and search for “glycogen storage disease” in the condition or disease field.

MDA’s Resource Center provides support, guidance, and resources for patients and families, including information about glycogen storage diseases, open clinical trials, and other services. Contact the MDA Resource Center at 1-833-ASK-MDA1 or ResourceCenter@mdausa.org.