Hypophosphatasia - pathophysiology and treatment

Area of Science:

• Biochemistry
• Genetics
• Pediatrics

Background:

• Hypophosphatasia (HPP) is an inherited metabolic disorder resulting from mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNAP).
• HPP presents with varying severity and age of onset, including perinatal, infantile, and childhood forms, often leading to severe rickets, respiratory failure, and seizures.
• The core biochemical defect is TNAP deficiency, causing elevated inorganic pyrophosphate (PPi), which inhibits calcification.

Purpose of the Study:

• To evaluate the efficacy of enzyme replacement therapy (ERT) using mineral-targeting TNAP (asfotase alfa) in a mouse model and human patients with HPP.
• To assess the impact of asfotase alfa on survival, skeletal development, neurological symptoms, and overall function in severe HPP.

Main Methods:

• Administration of mineral-targeting TNAP (asfotase alfa) to HPP mouse models (Alpl mice) from birth.
• Clinical trials involving children with life-threatening HPP, aged 3 years or younger, receiving asfotase alfa therapy.
• Monitoring of survival rates, seizure activity, rickets, dental abnormalities, respiratory function, and motor function.

Main Results:

• In the HPP mouse model, asfotase alfa administration increased survival and prevented rickets, seizures, and dental defects.
• Clinical trials demonstrated healing of skeletal manifestations and improved respiratory and motor function in young children with severe HPP.
• Continued asfotase alfa therapy showed ongoing improvement in patients, with some receiving treatment for over three years.

Conclusions:

• Enzyme replacement therapy with asfotase alfa is a promising treatment for severe, life-threatening hypophosphatasia.
• Asfotase alfa effectively addresses the underlying biochemical defect and improves clinical outcomes, including skeletal, respiratory, and neurological symptoms.
• Long-term asfotase alfa treatment appears safe and beneficial for patients with HPP.