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New Advances in Gene Therapy for Hypophosphatasia Treatment
For the past decade, the primary treatment for hypophosphatasia (HPP) has revolved around an enzyme replacement therapy requiring frequent injections, typically administered three to six times weekly.
“The therapy has shown remarkable efficacy and has saved countless lives,” stated José Luis Millán, PhD, a professor at the Human Genetics Program at Sanford Burnham Prebys. “Numerous children who underwent this treatment, who would have otherwise faced a fatal prognosis shortly after birth, are now thriving and looking forward to fulfilling lives.”
Despite its successes, the treatment can be invasive, and some patients experience adverse reactions due to the frequent injections, which leads some to discontinue the therapy. This challenge has spurred researchers to seek more advanced treatment options for HPP.
Hypophosphatasia, often referred to as soft bone disease, is a rare genetic disorder marked by abnormal bone development and early tooth loss. The severity of HPP can vary significantly; milder cases may leave adults prone to fractures, while more severe forms can lead to life-threatening complications in approximately one in 100,000 live births.
Currently, patients receive asfotase alfa, a specialized form of tissue-nonspecific alkaline phosphatase (TNAP), which is crucial for bone health. This FDA-approved treatment stems from Millán’s extensive research into TNAP and his laboratory’s work demonstrating its preclinical safety and efficacy.
“We envision the next phase in combating HPP to be a gene therapy approach wherein a single injection could provide lifelong treatment for patients,” explained Millán.
In a paper published on January 12, 2025, in the Journal of Bone and Mineral Research, Millán and his collaborators provided further validation for the safety and effectiveness of gene therapy targeting HPP.
The study explored AAV8-TNAP-D10, a specially engineered virus designed to deliver a gene capable of producing the missing TNAP enzyme, thereby reversing bone and dental malformations. While earlier research from Millán’s laboratory had laid the groundwork for this approach, the recent study aims to refine the upcoming clinical trials by experimenting with various dosages, assessing impacts in both male and female models, and considering different onset scenarios of HPP.
“We have meticulously adjusted the viral vector to determine which dosage yields effective results without leading to adverse effects like ectopic calcifications in soft organs,” stated Millán. “Our findings establish a solid foundation for forthcoming clinical trials.”
Interestingly, the research unveiled a noteworthy observation: in mouse models predisposed to late-onset HPP, the gene therapy appeared more effective in females, who achieved positive results with a lower dosage compared to males.
When analyzing the effects of the therapy, the research team discovered that adult female mice showed heightened enzymatic activity in the limb muscle, the precise location of the viral vector injection. In contrast, male mice exhibited the greatest enzymatic activity in the liver.
“During my presentation of this sexual dimorphism at the American Society for Bone and Mineral Research in Toronto last year, several clinicians remarked that while this trait is recognized in mice, it does not manifest in non-human primates or humans,” commented Millán. “While we do not expect this phenomenon to appear in future clinical trials, it is important for trial observers to be aware of its potential.”
With thorough preclinical research now published, Millán and his long-time collaborators, Drs. Takashi Shimada and Koichi Miyake from Nippon Medical School in Japan, aim to partner with a biopharmaceutical company to propel AAV8-TNAP-D10 into clinical trials. Additionally, Millán is focusing on further research to anticipate long-term complications that HPP patients may encounter in the coming years.
“We now have patients who are likely to live longer lives due to enzyme replacement and forthcoming therapies, yet we can only address the issues of skeletal mineralization. The missing enzyme plays critical roles in the brain, liver, kidneys, immune system, and beyond,” he added.
“This is what concerns me the most now. We need to be proactive in predicting potential long-term complications to ensure we can support HPP patients throughout their lives.”
This research was funded by the National Institutes of Health, Aruvant Pharmaceuticals, and the Endocrine Fellows Foundation.
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