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

Mayra A Carrillo; Shallu Tomer; Li Wang; Ethan Cook; Wally Wennerberg; Nicholas Tien; Hwee Ng; Jeyashree Alagarsamy; Valerie Rezek; Heather Martin; Sonoko Narisawa; Jose Luis Millan; Phillipe Crine; Michael Yan; Steven Lee; Na Jeong Kim; Ryan Rodriguez; Peyton Bishop; Romny Sanchez; Joey Orpilla; Virginia Le Verche; Shili Xu; Irvin S Y Chen; Scott Kitchen; Louis Breton; Jeffrey S Bartlett; Minh-Ha Do; Anjie Zhen

doi:10.1016/j.ymthe.2026.03.008

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

Mol Ther. 2026 Mar 10:S1525-0016(26)00193-0. doi: 10.1016/j.ymthe.2026.03.008. Online ahead of print.

Authors

Mayra A Carrillo¹, Shallu Tomer¹, Li Wang¹, Ethan Cook¹, Wally Wennerberg¹, Nicholas Tien¹, Hwee Ng¹, Jeyashree Alagarsamy¹, Valerie Rezek¹, Heather Martin¹, Sonoko Narisawa², Jose Luis Millan², Phillipe Crine³, Michael Yan³, Steven Lee³, Na Jeong Kim³, Ryan Rodriguez³, Peyton Bishop³, Romny Sanchez³, Joey Orpilla³, Virginia Le Verche³, Shili Xu⁴, Irvin S Y Chen¹, Scott Kitchen¹, Louis Breton³, Jeffrey S Bartlett³, Minh-Ha Do³, Anjie Zhen⁵

Affiliations

¹ Division of Hematology/Oncology, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, USA; UCLA AIDS Institute and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
² Sanford Children's Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
³ Rampart Bioscience Inc., Monrovia, CA, USA.
⁴ Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.
⁵ Division of Hematology/Oncology, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, USA; UCLA AIDS Institute and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Electronic address: azhen@mednet.ucla.edu.

PMID: 41814653
DOI: 10.1016/j.ymthe.2026.03.008

Abstract

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.

Keywords: HSPC therapy; TNALP; cell and gene therapy; hematopoietic stem and progenitor cells; hypophosphatasia; hypophosphatasia mouse model; lentiviral vector.