Gene therapy may be “one shot stop” for rare bone disease

(Press-News.org) For the last 10 years, the only effective treatment for hypophosphatasia (HPP) has been an enzyme replacement therapy that must be delivered by injection three-to-six times each week.

“It's been a tremendous success and has proven to be a lifesaving treatment,” said José Luis Millán, PhD, professor in the Human Genetics Program at Sanford Burnham Prebys. “Many children who have been treated otherwise would have died shortly after birth, and they are now able to look forward to long lives.

“It is, however, a very invasive treatment. Some patients have reactions from frequent injections and discontinue treatment. That has motivated us to find the next step in treating this disease.”

HPP — also known as soft bone disease — is a rare inherited disorder that causes abnormal development of bones and premature loss of teeth. HPP ranges in severity. Milder cases put affected adults at greater risk of breaking bones. Severe forms of the condition cause life-threatening disease in approximately one per 100,000 live births.

Currently, patients are treated with injections of asfotase alfa, a mineral-targeted form of the missing enzyme called tissue-nonspecific alkaline phosphatase (TNAP). This FDA-approved therapy is based on Millán’s decades of research on the TNAP enzyme and his laboratory’s studies demonstrating preclinical safety and efficacy.

“We believe the next evolution in treating HPP will be a gene therapy in which a single injected dose will provide a lifelong treatment for patients,” said Millán.

In a paper published January 12, 2025, in the Journal of Bone and Mineral Research, Millán’s team and collaborators added additional weight to prior preclinical evidence of the safety and effectiveness of a gene therapy for HPP.

The new study focused on AAV8-TNAP-D10, a virus engineered to not cause disease but rather to deliver a gene capable of producing the missing TNAP enzyme and reversing the malformation of bones and teeth. While previous research in the Millán lab had demonstrated the safety and effectiveness of this approach, the new investigation is intended to inform future clinical trials by including different dosages of the gene therapy, tests in male and female mice, and examinations in early- and late-onset forms of HPP.

“We have essentially titrated the viral vector to show which dose achieves efficacy without causing side effects such as accumulations of bony crystals in soft organs called ectopic calcifications,” said Millán. “Our data provide a clear starting point for clinical trials.”

The research team also noted one unexpected finding. In mice modeled to develop late-onset HPP as adults rather than infants, the gene therapy was more effective on female mice, and in females the improvements in bone and teeth were achieved with a lower dose of the treatment.

The scientists then compared the location of new enzymatic activity spurred by the gene therapy. In adult female mice with late-onset HPP, the greatest amount of activity occurred in the limb muscle, the site of injection of the viral vector. In males, however, the most activity was found in the liver.

“When I presented the data regarding this sexual dimorphism at the American Society for Bone and Mineral Research in Toronto last year, several physicians shared that this phenomenon is known in mice but does not happen in non-human primates or humans,” said Millán. “We don’t anticipate seeing this in future clinical trials, but now those monitoring the trials will be aware of the possibility.”

With ample preclinical research now established in the scientific literature, the next step is for Millán and his longtime collaborators — Drs. Takashi Shimada and Koichi Miyake of Nippon Medical School in Japan — to engage with a company capable of advancing AAV8-TNAP-D10 into clinical trials. Millán also is focused on future research to understand long-term complications that patients with HPP may face in the next few decades.

“We have patients now that will have long lives thanks to enzyme replacement and future therapies, but we’re only able to fix the skeletal mineralization. We know the missing enzyme also is expressed in the brain, the liver, the kidney, the immune system and elsewhere.

“That is what occupies my mind right now. We need to anticipate long-term problems before they happen so we can be prepared to help patients with HPP throughout their lives.”

Additional authors on the study include:

Flavia Amadeu de Oliveira, Cintia Kazuko Tokuhara and Sonoko Narisawa from Sanford Burnham Prebys Fatma F. Mohamed, Elis J. Lira dos Santos, Natalie L. Andras and Brian L. Foster from The Ohio State University Mohammad Shadid from Korro Bio Koichi Miyake from Nippon Medical School The study was supported by the National Institutes of Health (R01 DE12889, R21 DE031889, AG0811167, R01 DE032334), Aruvant Pharmaceuticals and the Endocrine Fellows Foundation.

The study’s DOI is 10.1093/jbmr/zjaf005.

The Journal of Bone and Mineral Research published a commentary on this study on February 2, 2025, titled, “Novel therapeutic options for hypophosphatasia.” Wolfgang Högler, MD, chair of Pediatrics at Johannes Kepler University in Austria, and Lothar Seefried, MD, head of the department of Osteology and clinical research at Julius-Maximilians University Würzburg in Germany, authored the article.

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