Enzyme-replacement therapy in life-threatening hypophosphatasia.

Question

1. what is the role of pyrophosphate in hypophosphatasia?

2. Why did the researchers consider that avoiding excess alkaline phosphatase was important?

3. What were the reasons for the withdrawal of consent for treatment?

4. What is the effect of etidronate on hypophosphatasia?

Accepted Answer

Markedly increased circulating pyridoxal–5′–phosphate levels in hypophosphatasia: alkaline phosphatase acts in vitamin B6 metabolism.

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15 Avoiding extraskeletal excesses of alkaline phosphatase seemed important because diminished extracellular production of inorganic pyrophosphate causes generalized arterial calcification of infancy.

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Treatment FindingsConsent for treatment was withdrawn for 1 of the 11 patients because of irritability, oxygen desaturation, rigors, and low-grade fever during receipt of the intravenous dose.

Accepted Answer

Muscle weakness, hyperphosphatemia, and osteomalacia that are reminiscent of hypophosphatasia occur with toxic doses of the first-generation bisphosphonate, etidronate (a synthetic analogue of inorganic pyrophosphate),37,38 suggesting that an accumulation of inorganic pyrophosphate in hypophosphatasia may have a myopathic effect.

Accepted Answer

ENB-0040 appears to be a potential enzyme-replacement therapy in patients with life-threatening hypophosphatasia, a metabolic bone disease.

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Three serious adverse events (one case each of respira-tory distress, craniosynostosis, and conductive hearing loss) were considered by the investigators to be possibly related to the study treatment.

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For life-threatening hypophosphatasia, attempts to transplant cells derived from healthy mesenchyme to form TNSALP-replete osteoblasts appeared to benefit, but not cure, two girls with infantile hypophosphatasia.

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The authors were concerned that subcutaneous injections of ENB-0040 might precipitate calcium and phosphate locally, because especially high levels of alkaline phosphatase would be present transiently near fibrillar collagen,40 but this was not observed.

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In conclusion, ENB-0040, a recombinant human TNSALP coupled to a deca-aspartate motif for bone targeting, was administered by one intravenous infusion and then subcutaneous injections in children with perinatal or infantile hypophosphatasia.

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After the start of therapy, deciduous teeth erupted in all the patients, with only one patient having hypophosphatasia-related loss of a tooth.

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1In this study, the authors found that bone-targeted enzyme replacement with ENB-0040 was effective in infants and young children with life-threatening or severely debilitating hypophosphatasia.

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For each patient, the mean score among the radiologists was used for analysis, with a response to treatment defined as a mean increase of 2 or more points (i.e., substantial healing).

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Substantial radiographic improvement in skeletal abnormalities was noted at week 24 in all but one patient, with continued healing through week 48.

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It is possible that the improved motor function in their patients reflected hydrolysis of inorganic pyrophosphate or some as-yet-unrecognized TNSALP substrate.39

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This delay probably reflected the profound deficit of skeletal mineral in the patient, although sufficient hydroxyapatite was apparently present for targeting with ENB-0040.

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Changes from baseline were calculated at weeks 24 and 48, with the use of Wilcoxon signed-rank tests to determine whether median changes differed from 0 (see the Supplementary Appendix).

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Plasma levels of inorganic pyrophosphate were measured before and after treatment in five patients; the median level decreased from 5.2 nM at baseline to 1.1 and 1.9 nM at weeks 24 and 48, respectively (see the Supplementary Appendix).

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The proportion of patients with a response, with the 95% exact confidence interval, was calculated at weeks 24 and 48.31 Two-sided Wilcoxon signedrank tests32 were used to determine whether the median scores differed from 0 (i.e., no change).

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Consent for treatment was withdrawn during the initial intravenous infusion of ENB-0040, and the patient received no further treatment.

Accepted Answer

Despite the presence of calcification in the kidneys of eight patients at baseline, no new occurrences of nephrocalcinosis were reported, and nephrocalcinosis resolved in one patient.

Enzyme-replacement therapy in life-threatening hypophosphatasia.

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Most frequently asked questions

1. what is the role of pyrophosphate in hypophosphatasia?

2. Why did the researchers consider that avoiding excess alkaline phosphatase was important?

3. What were the reasons for the withdrawal of consent for treatment?

4. What is the effect of etidronate on hypophosphatasia?

5. What is the role of ENB-0040 in the treatment of hypophosphatasia?

6. What were the adverse events considered to be related to the study treatment?

7. What did the researchers find to be the effective treatment for hypophosphatasia?

8. Why did the authors not observe a decrease in calcium and phosphate levels in the patients?

9. What is the effect of ENB-0040 on the skeletal system?

10. What was the cause of the delay in the treatment of the patients?

11. What was the effect of ENB-0040 on the skeletal system?

12. What was the mean score for each patient?

13. What was the effect of ENB-0040 on the skeletal abnormalities?

14. What is the reason for the delay in motor function in the patients?

15. What was the cause of the delay in the treatment of hypophosphatasia?

16. How did the changes from baseline differ from 0?

17. What is the median level of pyrophosphate in the chest?

18. What was the median score of the patients with a response to treatment?

19. What was the patient's response to ENB-0040?

20. What is the reason for the delay in nephrocalcinosis?

Figures

Citations

Chapter 35 – Mineral Metabolism

Bildgebende Diagnostik kindlicher Knochenerkrankungen

Efficacy of World Health Organization Guideline in Facility-Based Reduction of Mortality in Severely Malnourished Children From Low and Middle Income Countries.

Adult hypophosphatasia manifests in a marathon runner.

Methods to Characterise Enzyme Kinetics with Biological and Medicinal Substrates: The Case of Alkaline Phosphatase

References

Individual Comparisons by Ranking Methods

The use of confidence or fiducial limits illustrated in the case of the binomial

Principles of bone biology

Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone

Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification

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