HPP Archives - Sanford Burnham Prebys

Tag: HPP

Institute News

Guglielmi awarded grant to further investigate genetic condition that results in soft, deformed bones and lost teeth

AuthorScott LaFee
Date

January 9, 2025

Valeria Guglielmi profile photo
Valeria Guglielmi, PhD, postdoctoral associate in the D’Angelo lab.

Hypophosphatasia (HPP) is a rare genetic disorder in which bones and teeth fail to take up sufficient calcium and phosphorus needed to achieve proper hardness and strength. Defective mineralization results in bones that are soft and prone to fracture and deformity, and the loss of teeth. Occasionally, HPP can cause death due to complications.

Prevalence varies by severity and age of onset. It is rarest but most severe at birth (1 in 100,000 live births), with lower prevalence and milder forms in later years. The condition can manifest at any age.

The cause of HPP is a mutation in an enzyme called tissue-nonspecific alkaline phosphatase (TNAP), which plays a critical role in skeletal and dental mineralization. In 2015, an enzyme replacement therapy developed by José Luis Millán, PhD, a professor in the Human Genetics Program at Sanford Burnham Prebys, was approved to treat pediatric onset HPP, dramatically improving patients’ lifespan and quality of life.

But the effects of TNAP deficiency appears to extend beyond faulty mineralization. HPP patients also experience altered immune responses, suggesting TNAP might have a role in immune cells.

Recently, Soft Bones, an advocacy group for HPP patients, awarded Valeria Guglielmi, PhD, a postdoctoral associate in Maximiliano D’Angelo’s lab, with a one-year, $25,000 seed grant to further investigate the involvement of TNAP in inflammatory responses and immune cell functions.

“This study is in line with my broad interest  for immune cells and their contribution to tissue homeostasis and diseases,” said Guglielmi. “I am excited to explore an entirely new area of investigation on HPP.

“Indeed, very little is known about the role of TNAP in the immune system and only a few studies have provided evidence of TNAP involvement in immune cell function. By uncovering how TNAP deficiency affects inflammatory responses, our research represents the first step toward designing interventions to improve immune system dysfunctions in HPP patients.”

Read Soft Bones’ full news release on the award to Guglielmi on Facebook and Instagram.

Institute News

SBP scientist honored by the American Society for Bone and Mineral Research

AuthorMonica May
Date

September 28, 2018

José Luis Millán, PhD

José Luis Millán, PhD, professor in the Human Genetics Program at Sanford Burnham Prebys Medical Discovery Institute (SBP), has received the 2018 American Society for Bone and Mineral Research (ASBMR) Lawrence G. Raisz Award for his outstanding achievements in pre-clinical and translational research. 

Millán has dedicated his career to understanding the mechanism of initiation of skeletal and dental mineralization. His pioneering research has led to the first-ever FDA-approved drug for a rare soft bone disease, hypophosphatasia (HPP); and a second drug candidate developed through a research collaboration with Daiichi Sankyo Company, Limited (Daiichi Sankyo) that entered a Phase 1, first-in-human clinical trial in 2017. 

ASBMR’s award is named in honor of Lawrence G. Raisz, MD, a prominent scientist, mentor, teacher and clinician in the field of bone and mineral metabolism. Raisz was a founding member of ASBMR and the first editor-in-chief of the Journal of Bone and Mineral Research. 

“Lawrence G. Raisz deeply influenced the skeletal mineralization field, so it is a true honor to receive an award in his memory,” says Millán. “In accepting this award, I want to thank the many individuals who enabled our achievements—from the National Institutes of Health (NIH), which has generously funded our research since the 1980s, to the collaborators and lab members who were instrumental in our scientific advances. I also want to thank SBP for providing state-of-the-art technologies that were invaluable to our research.”

Millán was presented the award onstage today at the ASBMR 2018 Annual Meeting in Montreal. 
 

Interested in keeping up with SBP’s latest discoveries, upcoming events and more? Subscribe to our monthly newsletter, Discoveries.

Institute News

Soft bone disease research — from bench to bedside and back

Authorjmoore
Date

April 7, 2016

Header image

Funding for the laboratory of José Luis Millán, PhD, professor in the Human Genetics Program, has been renewed by the NIH to the tune of $3 million over the next five years. The grant ensures that they can continue to advance understanding of and develop treatments for the rare disease called hypophosphatasia (HPP). This disease—also known as soft bones—can cause skeletal deformities of the limbs and chest and result in frequent fractures and premature loss of teeth. HPP is estimated to affect approximately one per 100,000 live births.

The Millán lab’s decades of research have already led to the first-ever treatment, asfotase alfa, an enzyme that’s injected three to six times per week to help harden bones. This drug is a functional version of the enzyme that’s defective or missing in HPP patients, tissue-nonspecific alkaline phosphatase, that is modified to help it reach mineralizing tissues such as bone. Asfotase alfa is manufactured by Alexion Pharmaceuticals and was approved by the FDA last year.

The new therapy has transformed the lives of patients who received it as part of the clinical trial. For example, San Diego’s own Morgan Fischer couldn’t walk before receiving it, but she has since started skiing, riding ponies, and joined a kids’ baseball team.

“It is a rare privilege for a basic research scientist like myself to be able to translate our laboratory work to the clinic and impact patients’ lives,” said Millán. “It’s been extremely rewarding to see how much this treatment has helped these children, and now also adults, afflicted by this genetic disorder.”

“But our work is not done.”

With their current NIH support, Millán’s research group will address asfotase alfa’s limitations. For one, it doesn’t prevent premature fusion of skull bones, which means that many patients still need surgery to allow the brain to grow properly. Investigating other factors regulating skull development could identify targets for future drugs that could be used in combination with enzyme replacement.

Another potential problem with asfotase alfa is that it may contribute to hardening of the arteries in adults. This may result from the way the enzyme is modified, which could also lead to accumulation in arteries. The researchers will examine whether alternative forms of the enzyme can lessen this effect.

“While our earlier research went from the bench to the bedside, now we’re taking what we’ve learned from patients back to the bench. Hopefully, our studies will lead to insights that allow hypophosphatasia patients to live long, healthy lives,” Millán added.