Lentivirus-based HPSC therapy provides effective and long-term treatment in hypophosphatasia mouse model.

Hypophosphatasia (HPP) is a multi-system metabolic disorder characterized by skeletal hypomineralization and perinatal lethality in severe cases and rickets, muscle weakness, and premature tooth loss in milder forms. It is caused by loss-of-function mutations in the ALPL gene encoding the tissue-nonspecific isozyme of alkaline phosphatase (TNALP). Currently, enzyme replacement therapy with asfotase alfa (STRENSIQ) is the only treatment approved for the most severe forms of the disease. It enhances survival and improves bone mineralization, but it is burdensome for the patients who must undergo daily, or every other day, injections for the rest of their lives. Alternative cell therapies are under development to overcome TNALP deficiency. Here, we report the development of a lentiviral vector (LVV), RMP100-LVV, to stably express soluble TNALP in LVV-transduced hematopoietic stem and progenitor cells (HSPCs). We show engraftment and differentiation of human RMP100-LVV-modified HSPCs in humanized mice and that treatment with this cell therapy approach leads to a durable correction of plasma alkaline phosphatase activity, rescues skeletal manifestations, and prevents early mortality in a severe HPP mouse model. Our study provides critical insights into treating metabolic bone disorders with an autologous HSPC-based gene therapy and demonstrates that this approach is a potential one-time treatment for HPP.