Pompe disease unmet needs and emerging therapies

Overview of Pompe disease

Pompe disease, sometimes referred to as acid maltase deficiency or Glycogen Storage Disease Type II, is a rare genetic disorder brought on by a mutation in the GAA gene that depletes acid alpha-glucosidase. This enzyme is necessary for lysosomal glycogen breakdown. Without it, glycogen builds up in skeletal, cardiac, and smooth muscles, damaging them.

Pompe disease with fish mouth

Pompe Disease Types

• Infantile-Onset (IOPD): <12 months. The symptoms include an enlarged heart, severe muscular weakness, and respiratory difficulties. Fatal without early treatment; rapid progression
• Late-onset (LOPD): Childhood–adulthood. Slow muscular weakening, respiratory failure, and no heart involvement. The severity of the condition varies, and its progression is slower.
• Increasing limb-girdle weakness. Difficulty ascending stairs or standing up, Weak respiratory muscles. Fatigue, frequent infections

Origin of Pompe Disease

• Gene Mutation
• The GAA gene lies on 17q25.3.
• The lysosomal enzyme acid alpha-glucosidase is reduced or eliminated by gene mutations.

Lack of Enzymes

• Glycogen in lysosomes is converted to glucose by GAA.
• Without adequate GAA, muscle cells store glycogen.

Pathophysiology

• Too much glycogen affects cell function.
• Over time, heart, diaphragm, and skeletal muscle cells deteriorate.
• Infants who suffer from this develop cardiomyopathy, respiratory issues, and muscle weakness.

Genealogy

Recessive autosomal.  Two faulty copies of the GAA gene from each parent are necessary for Pompe disease to manifest.

Carriers with one defective gene rarely exhibit symptoms.

What is the Pompe disease lifespan?

Pompe disease's life expectancy depends on the type of treatment, the severity of the condition, and the timing of intervention, particularly with enzyme replacement therapy.

Life Expectancy by Type: 

• Infantile-Onset Pompe Disease (IOPD)
• Most infants with classic IOPD die before 18 months from cardiac and respiratory failure without therapy.
• Early enzyme replacement therapy (ERT) can extend survival into childhood and beyond, depending on when the therapy starts and how complications are managed.

Late-onset Pompe Disease

• Symptoms may emerge in childhood, adolescence, or maturity.
• Progressive skeletal and respiratory muscle weakening without cardiac involvement.

ERT and multidisciplinary treatment let many people live into late adulthood, but respiratory failure is a danger.

Key Factors Influencing Life

• Timing of diagnosis and treatment
• Deficiency of enzymes severity
• Cardiovascular and respiratory issues
• Physical therapy, ventilatory support
• Adjustments to diet, exercise, and assistive technology

What are Pompe disease's early symptoms?

• Early Symptoms by Type: Classic Infantile-Onset Pompe Disease
• The first several months of life usually bring symptoms:
• Bad muscular tone and weakness (“floppy baby”)
• Feeding issues and failure
• Cardiomegaly and hypertrophic cardiomyopathy
• Respiratory issues
• Big tongue
• Liver enlargement
• Motor delays (not sitting, crawling, standing)
• Hypotonia-induced frog-leg posture

Non-Classic Infantile-onset

• Usually by age 1:
• Weakening muscles
• Motor milestone delays
• Respiratory issues
• No early cardiomyopathy cardiomegaly

Late-onset Pompe Disease

• Childhood, adolescence, or adulthood can cause symptoms:
• Reduced hip and shoulder strength
• Trouble getting up from a chair or stairs
• Fatigue, muscular pain
• Frequent respiratory infections
• Scoliosis or hyperlordosis might cause breathing issues during sleep.
• Hearing loss in some circumstances

Clinical Insight

The disease is more aggressive when symptoms occur early. Early detection—especially in infants—is essential for enzyme replacement therapy (ERT) before permanent harm.

Pompe disease: curable?

Although Pompe disease cannot be cured, it can be managed well with early intervention. Current status:

• No cure yet
• Pompe disease is caused by GAA gene mutations, which existing treatments cannot eradicate.
• Treatment focuses on enzyme replacement and symptom management, not illness elimination.

The video explains Gene therapy for Pompe disease

Standard Treatment: Enzyme Replacement Therapy

• ERT provides the synthetic acid alpha-glucosidase (GAA) to break down glycogen.
• Treatments approved include:
• Lumizyme (Myozyme): The first ERT
• Nexviazyme: Better-targeted second generation
• Pombiliti + Opfolda: Uptake-enhancing combination.

When administered early, enzyme replacement therapy (ERT) can prolong life, improve respiratory and motor function, and slow the progression of the disease.

New Therapies and Future Hope

• Gene therapy: Clinical trials with functional GAA gene copies.
• Chaperone therapies stabilize and improve residual GAA enzyme.
• Novel ERTs: Anti-transferrin receptor (TfR)-coupled GAA may pass the blood-brain barrier and improve mouse models.

Also, read https://www.buzzrx.com/blog/pompe-disease.

Pompe Disease Treatment Overview

1. ERT—Enzyme Replacement Therapy Cornerstone

• ERT synthesizes acid alpha-glucosidase (GAA) to decrease cell glycogen.
• Lumizyme (Myozyme): First-generation ERT enhances breathing and motor function
• Second-generation ERT Nexviazyme. Mannose-6-phosphate targeting Pombiliti + Opfolda combination therapy increases absorption, resulting in improved cellular delivery and longer-lasting effects.
• Infusion intravenously every two weeks
• Results are best when started early, especially in infantile-onset cases.

CRIM status matters:

• In CRIM-negative patients, ERT may cause immunological reactions.
• Immune modulation may boost tolerance.

2. Supportive, multidisciplinary

• Pompe disease involves numerous systems; hence, treatment is team-based.
• PT maintains strength and mobility
• Respiratory therapy: Aids breathing and sleep.
• Speech/occupational therapy: Promotes daily function and communication
• Nutritional help: Supports muscular health and prevents starvation

3. Emerging Therapies

• Research is improving focused and lasting treatments:
• Gene therapy: Directly delivers the functional GAA gene to cells.
• Chaperone molecules: Support residual enzyme activity

Enzyme replacement therapies (ERTs) that target the transferrin receptor (TfR) and can cross the blood-brain barrier are currently in preclinical stages.

Clinical Insight

• Lifelong treatment involves monitoring:
• Pulmonary function
• Motor milestones
• Cardiac status of CRIM-negative patients: antibody development

Pompe disease diagnosis

Step-by-Step Diagnosis of Pompe Illness: Enzyme Activity Testing Examines the faulty enzyme in Pompe Illness, acid alpha-glucosidase (GAA).

Common methods:

• Dry blood spot (DBS): Common newborn screening tool.
• Leukocyte or fibroblast assay: More detailed, used for confirmation.
• In infants, GAA activity is often less than 1% of normal.
• Activity may reach 40% of the typical late-onset.

2. Gene Testing

• Gene testing identifies GAA gene mutations to confirm the diagnosis.
• Samples: saliva or blood.
• Aids in determining CRIM status, which impacts ERT response.
• Family carrier status.

3. Clinical Assessment

• History and physical exam: Evaluate muscle weakness, respiratory problems, and heart signs.
• Heart tests: ECG and echocardiography for cardiomyopathy (particularly in newborns).
• Pulmonary function testing for respiratory muscle involvement.
• Although rarely used, muscle imaging or biopsy can reveal the presence of glycogen buildup.

4. Differential Diagnoses

Neuromuscular illnesses, including muscular dystrophies and spinal muscular atrophy, share Pompe symptoms.

Early misdiagnosis is frequently caused by the mild or slow progression of symptoms, particularly in late-onset diseases.

Pompe disease diet?

There's no common Pompe disease diet, but clinical experience and early research have suggested numerous ones.

• Dietary Guidelines for Pompe Disease
• Main Goals
• Decrease glycogen gain
• Maintain muscular mass
• Support breathing and swallowing
• Avoid obesity and malnutrition.

Advice on Nutrition

• High protein intake (20-30% of calories). Promotes muscle regeneration and glycogen reduction
• Carbohydrates: Complex carbohydrates, moderate to low consumption, restrict glycogen production.
• Omega-3s are healthy fats. Energy and anti-inflammatory support
• Timing: Small, frequent meals help prevent energy troughs and ensure metabolic stability.
• Swallowing Support Foods with texture and thickened liquids, manage infantile-onset dysphagia.
• Hydrate: Drink plenty. Supports respiratory and muscular function
• Sample Foods High in Protein
• Eggs, chicken, fish, lean meats
• Cheese, yoghurt
• Legumes, tofu, soy
• Nuts, seeds

Special Considerations

• Enteral nutrition or thickened drinks for dysphagia
• Weight tracking: Patients may be underweight or overweight due to muscle loss or movement issues.
• Individualized plans: Age, activity, and ERT affect diet.

Conclusion: Pompe Disease Knowledge

While there is no cure, early enzyme replacement therapy (ERT) has improved prognosis. Gene therapy, chaperone molecules, and targeted delivery systems studies may lead to more durable and tailored treatments.

Medical therapy, dietary assistance, physical rehabilitation, and respiratory care are needed for effective management. Improved outcomes depend on early detection, frequently through neonatal screening or genetic testing.