Enzyme replacement therapy for murine hypophosphatasia

Area of Science:

• Biochemistry
• Genetics
• Pediatrics

Background:

• Hypophosphatasia (HPP) is a genetic metabolic disorder caused by mutations in the tissue-nonspecific alkaline phosphatase (TNALP) gene.
• This leads to impaired bone mineralization, rickets, and potentially severe health issues in infants, with no current effective treatment.
• Accumulation of TNALP substrates, like inorganic pyrophosphate (PPi), inhibits mineralization, while reduced PLP can cause vitamin B6-dependent seizures.

Purpose of the Study:

• To evaluate the efficacy of a novel enzyme replacement therapy for infantile hypophosphatasia (HPP).
• To assess the therapeutic potential of a bioengineered, bone-targeted recombinant human TNALP (sALP-FcD10) in a relevant animal model.

Main Methods:

• TNALP was engineered with an Fc-human IgG fusion and a deca-aspartate sequence (D10) for tissue targeting (sALP-FcD10).
• TNALP-null (Akp2-/-) mice, modeling infantile HPP, received daily subcutaneous injections of sALP-FcD10 from birth.
• Efficacy was assessed through survival, growth, biochemical markers (calcium, PPi, pyridoxal), and skeletal/dental health evaluations.

Main Results:

• Mice treated with high-dose sALP-FcD10 exhibited normal growth and overall health.
• No significant skeletal or dental abnormalities were observed in the treated mice.
• Plasma levels of calcium, PPi, and pyridoxal remained within normal ranges, indicating successful metabolic correction.

Conclusions:

• Bone-targeted enzyme replacement with recombinant human TNALP (sALP-FcD10) effectively prevents infantile HPP in a mouse model.
• This therapeutic strategy demonstrates potential for treating HPP by restoring TNALP activity in mineralizing tissues.