Hypophosphatasia

Hypophosphatasia is a rare, and sometimes fatal inherited metabolic disease characterized by a defect in bone mineralization. The disease is caused by mutations in the gene encoding an enzyme called tissue non-specific alkaline phosphatase (TNSALP).  The resulting TNSALP deficiency impairs bone mineralization leading to “soft bones” (rickets in children and osteomalacia in adults) which are prone to fracture and deformity.  Clinical symptoms are heterogeneous ranging from a fatal perinatal form, with profound skeletal hypomineralization, extensive fractures and deformities and respiratory compromise to a milder adult form characterized by bone pain and stress fractures. 

Disease awareness is low likely leading to delayed and or possible misdiagnosis in many cases.  Genetic inheritance is largely autosomal recessive but autosomal dominant in some milder forms.  The prevalence of hypophosphatasia is not known with certainty.  One Canadian study estimated the prevalence of severe forms to be 1:100,000.

There is no approved therapy for hypophosphatasia.  Attempts at enzyme replacement therapy using serum from patients with high levels of TNSALP activity have been unsuccessful.  Bone marrow transplantation has been life-saving but has had limited impact on growth and other features of the disease.  The current treatment paradigm includes dietary restrictions of calcium intake and/or glucocorticoid therapy for the infantile form and supportive care.   

Enobia is developing an enzyme replacement therapy (ERT) for hypophosphatasia by targeting the TNSALP enzyme directly to bone where it is normally active.

Enobia has recently reported promising results in a mouse model of hypophosphatasia. [Annual Meeting of the International Bone and Mineral Society/June 2007, Annual Alkaline Phosphatase Symposium/May 2007].  When treated with recombinant, bone-targeted TNSALP, hypophosphatasia mice demonstrated improved:

• survival (reduction in seizures)
• weight gain
• dentition
• bone formation and growth