Research

HPP Research

Soft Bones funds research to better understand HPP with the goal of finding a cure. 

We believe a cure is possible

With modern-day science of gene editing and gene therapy, we work closely with researchers and clinicians to champion collaboration, reduce duplication of effort, share findings and unite the global HPP community. We also work to position HPP as a favorable subject of research through a global HPP registry. Areas we support include:

HPP Patient Registry

Soft Bones has partnered with Coordination of Rare Diseases at Sanford (CoRDS) to create an International HPP Contact Registry. The registry provides patients and caregivers with a secure means of making their basic disease information available to researchers without sacrificing privacy. By joining the registry, you can help researchers see the whole picture and gain valuable information for a disease that they know too little about. Information learned through the registry plays a vital role in improving treatments and finding a potential cure.

For more information, contact CoRDS at cords@sanfordhealth.org or (877) 658-9192.

You can also access the
CoRDS Participant Brochure,
CoRDS Registration Tip Sheet
CoRDS Podcast Info Card.
Once ready, you may register using the link below, or call the CoRDs office directly.

Soft Bones Grant Winners

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Nan Hatch, DMD, PhD
2022

Mohamed-bw

Fatma F.Mohamed, PhD
2021

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Flavia Amadeu de Oliveira, PhD
2020

dana

Dana Gaddy, PhD
2019

dob

Dobrawa Napierala, PhD
2019

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Kathryn Dahir, MD
2017

brian

Brian Foster, PhD
2016, 2018

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Luke Mortensen, PhD
2015

stephen

Steven Mumm, PhD
2014

Nan Hatch, DMD,PhD University of Michigan School of Dentistry- 2022

2022 Recipient – Nan Hatch, DMD, PhD, an associate professor of dentistry at the University of Michigan School of Dentistry. The grant will support Dr. Hatch’s studies to establish essential roles for tissue-nonspecific alkaline phosphatase (TNAP) in muscles and determine how TNAP modulates muscle function.

Fatma F. Mohamed, PhD
The Ohio University College of Dentistry- 2021

2021 Recipient- Fatma F. Mohamed, PhD, The Ohio State University College of DentistryDr. Mohamed’s research will investigate the nervous system using new mouse models of HPP to uncover the roles it might have in the formation, maintenance, and repair of dental and skeletal tissues. “This grant will open a new avenue for further investigation on HPP’s influence on the nervous system and allow for evaluation of enzyme replacement efficacy in such specific contexts,” said Dr. Mohamed. “With new models and a better understanding of HPP, we can generate new ideas; I am excited to get started.”

Dr. Mohamed’s research will investigate the nervous system using new mouse models of HPP to uncover the roles it might have in the formation, maintenance, and repair of dental and skeletal tissues. “This grant will open a new avenue for further investigation on HPP’s influence on the nervous system and allow for evaluation of enzyme replacement efficacy in such specific contexts,” said Dr. Mohamed. “With new models and a better understanding of HPP, we can generate new ideas; I am excited to get started.”

Flavia Amadeu de Oliveira, PhD
Sanford Burnham Prebys Medical Discovery Institute- 2020

2020 Recipient – Flávia Amadeu de Oliveira, PhD, Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California The study objectives look to determine the efficacy of viral vector delivery of mineral-targeted tissue non-specific alkaline phosphatase (TNAP) to treat late onset or adult HPP.”I have a long-standing interest in bone biology, especially in the molecular mechanisms that regulate bone homeostasis,” said Dr.Amadeu de Oliveira.

. “Overall, my goal through this research proposal is to test if chronic administration of mineral-targeted TNAP in HPP mice with superimposed chronic kidney disease, which manifests vascular calcification, may have adverse consequences. In doing so, I will also attempt to validate viral vector delivery of mineral-targeted TNAP to correct the soft bones disease in late-onset HPP mice. Overall, this study will contribute to devising safe and improved therapies for HPP,” she continued.”Overall, my goal through this research proposal is to test if chronic administration of mineral-targeted TNAP in HPP mice with superimposed chronic kidney disease, which manifests vascular calcification, may have adverse consequences. In doing so, I will also attempt to validate viral vector delivery of mineral-targeted TNAP to correct the soft bones disease in late-onset HPP miceOverall, this study will contribute to devising safe and improved therapies for HPP,” she continued.The Scientific Advisory Board for Soft Bones carefully considers grant applications and this year solicited submissions that would help advance gene therapy in HPP.
“The implications of this work may extend to all forms of HPP, not just adult,” says Dr.Jose Luis Millan, Soft Bones Scientific Advisory Board member and Professor of Human Genetics at Sanford Burnham Prebys Medical Discovery Institute. “The findings could be relevant to the entire HPP spectrum.” 

Dana Gaddy, PhD
Texas A&M University- 2019

2019 Recipient – Dana Gaddy, PhD, Texas A&M University Dr. Dana Gaddy, in collaboration with her co-investigators Dr. Sarah White and Dr. Larry Suva, will conduct research using their novel findings of muscle structure and ultrastructural defects in sheep with HPP to determine the cause of muscle weakness commonly seen, but poorly understood, in HPP patients.

The Scientific Advisory Board for Soft Bones considers grant applications and oversees material development to ensure medical accuracy and provide strategic guidance for research grants. The board, comprised of internationally known, multi-disciplinary experts, is chaired by Michael P. Whyte, M.D., Medical-Scientific Director at the Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children and Professor of Medicine, Pediatrics and Genetics at Washington University School of Medicine in St. Louis, MO.

“A significant appeal of Dr. Gaddy’s proposal is that it moves closer toward the HPP patient,” said Dr. Whyte.  “Prior to this, the only animal model was in mice. The sheep model is more ideal for examining bone and dental changes that affect HPP patients and could ultimately lead to therapeutic innovations benefitting patient outcomes,” he added.

Dobrawa Napierala, PhD
University of Pittsburgh School of Dental Medicine- 2019

2019 Recipient – Dobrawa Napierala, PhD, University of Pittsburgh – This grant will fund a research project conducted  to address the novel role of tissue-nonspecific alkaline phosphatase (TNSALP) in the mineralization process, which is the underlying cause of the majority of skeletal deformities and dental problems in HPP patients.

“My ultimate goal is to understand the molecular bases of human disorders affecting the formation of bone and teeth for the improvement of therapeutic approaches,” said Dr. Napierala. “This grant will allow me to explore the novel, previously unrecognized, function of alkaline phosphatase in bone and tooth cells, as I seek to help identify new treatment approaches that are applicable to various bone and tooth formation diseases.”

“Dr. Napierala’s research aims to provide a better understanding of molecular mechanisms underlying genetic mineralization disorders including rickets, osteomalacia and, most importantly for Soft Bones, HPP,” noted Dr. Whyte. “Her research may provide a premise for evaluating TNSALP as potential treatment for these disorders.”

Kathryn Dahir, MD
Vanderbilt University Medical Center-2017

2017 Recipient – Dr. Kathryn Dahir, MD, Vanderbilt University Medical CenterDr. Kathryn Dahir, an adult endocrinologists and bone specialist at Vanderbilt University Medical Center in Nashville, Tennessee, and colleagues study adolescents and adults with HPP.”We are excited to receive this grant, which will allow us to directly study physical impairments, abnormalities in movement and cognitive deficits in both adolescents and adults with HPP,” said Dr. Dahir. “Findings from this study will be used to develop strategies for patients, families and their doctors to better identify problems and make appropriate referrals to specialists when needed,” she continued.

The study is a collaborative effort between adult and pediatric endocrinology and the Pi Beta Phi Rehabilitation Institute. In addition, Dr. Dahir and colleagues are partnering with the Biomechanics & Assistive Technology Laboratory at Vanderbilt University to use state-of-the-art 3D motion analysis equipment to test for abnormalities in gait and muscle weakness in adolescents and adults with HPP.

The Scientific Advisory Board for Soft Bones carefully considers grant applications and after thoroughly reviewing Dr. Dahir’s study, the board agreed that more individualized research is needed to better understand how diverse the problems of HPP in adults can be.

Brian Foster

Brian Foster, PhD
The Ohio State University- 2016,2018

2016 and 2018 Recipient – Brian Foster, Ph.D., The Ohio State University 2016 – I study the biology of tooth development, focusing on factors that are important for proper tooth formation and function. My emphasis is on the mineralized (hard) tissues of the tooth that give it mechanical strength- the enamel, dentin, cementum, as well as the bone that forms the socket around the tooth. By better understanding how teeth develop, I hope to gain new insights that may one day improve approaches for repair and regeneration of dental tissues.

Many people with HPP experience dental problems associated with the disease. A greater understanding of the effects of HPP on the bones and teeth has been gained from studies using a mouse model of HPP. This mouse model is a good representation of severe infantile HPP, however the severity of the disease prevents long-term studies, including those on therapies that may treat HPP-associated dental disease. As part of the Soft Bones research grant proposal, we aim to create new mouse models of HPP that vary in the severity of disease and location of tissues affected. These will include models that affect the bones and teeth, as well as those that primarily target the dental tissues. The novel HPP mouse models will then allow better controlled studies of how different therapies can prevent and repair HPP-associated skeletal and dental problems. These models will allow expansion of HPP research by additional researchers in the future, thus providing new resources to widen HPP-related research. With the support of the Soft Bones 2016 Research Grant, we have been able to analyze two new mouse models for dental disorders associated with HPP. The original mouse model of HPP that has been used for two decades has provided a wealth of information about all aspects of the disease, however, was limited by its severity that shortened its lifespan and restricted the types of studies that could be performed. These new HPP mouse models, developed in part with the grant, replicate the effects of HPP on bone and tooth development, but the later disease onset and targeted effects on hard tissues has translated into longer-lived HPP models that can be studied over a longer period to more advanced ages. One insight already provided by these novel models relates to the development of periodontal disease around teeth that have been affected by HPP. This work was recently published in the January 2017 issue of the Journal of Dental Research, one of the top ranking scientific journals in the field of Dentistry, Oral Surgery & Medicine.

2018 – As the recipient of a 2018 research grant from Soft Bones, Dr. Foster, in collaboration with Dr. Michael White, an Endocrinologist at Shriners Hospital for Children and Washington University in St. Louis, proposes to analyze primary teeth (deciduous or baby teeth) from individuals with hypophosphatasia (HPP). This study is the first of its kind to quantitatively analyze teeth from a large group of HPP subjects. Dr. Foster hopes to gain a better understanding of how dental problems correlate to skeletal, biochemical and genetic changes in individuals with HPP. In the future, this may help medical professionals predict the severity of HPP-associated dental disease, better treat dental disorders arising from HPP, or even estimate the overall course of disease.With this project, Dr. Foster and his team will continue building upon years of achievement in the field of HPP research, with a specific focus on the relationship between HPP and dental disorders. For several years, Dr. Foster has been studying mouse models of HPP to understand how the disorder affects the different hard tissues of teeth and supporting jaws, including enamel, dentin, cementum and bone. Dr. Foster won the 2016 Soft Bones research grant for his mouse model research, and the 2016 grant supported development of a new mouse model of HPP that was featured in the Journal of Dental Research.

Luke Mortensen, PhD
University of Georgia- 2015

2015 Recipient – Luke Mortensen, Ph.D., The University of Georgia Stem Cells, or MSCs, are an adult stem cell type that produce bone, cartilage, and fat. These cells can be harvested from adults, and easily expanded to generate millions of cells from just a single donor. The potential to make new healthy bone has led to their study as a potential therapeutic for bone diseases like osteoporosis and osteogenesis imperfecta.

The goal of MSC therapy is to inject cells from a healthy donor into a patient with impaired bone formation, with the goal of the transplanted cells traveling to the diseased bone sites and integrating into the tissue to form strong healthy bones. However, these MSC therapies have had limited success due to small proportions of the transplanted cells arriving at the target destination and limited survival of these transplanted cells. In hypophosphatasia (HPP), little has been reported on MSC therapy. With the support of the Soft Bones Foundation Maher Family Grant, the Mortensen lab has used our advanced microscopes to evaluate the potential of MSC therapy in a mouse juvenile HPP model. We track labeled MSCs to the bone marrow in mice with single cell resolution. We have investigated the effect of MSC therapy on the mortality and weight gain of severe HPP that is typically fatal by 3 weeks of age. We are currently working to develop high resolution imaging of living bone quality using a cutting-edge technology called second harmonic generation to understand the effect of HPP on bone organization and the potential effects of MSCs and other therapeutics on this structure. Additionally, ongoing experiments aim to enhance the receptiveness of bone marrow to improve transplanted cell survival, and to engineer MSCs to enhance their homing and survival in the bone.

Steven Mum, PhD
Washington University School of Medicine- 2014

2014 Recipient – Steven Mumm, Ph.D., Washington University School of MedicineThe Soft Bones Foundation research grant helped us complete DNA sequencing of the tissue non-specific alkaline phosphatase gene (TNSALP or ALPL) for our pediatric hypophosphatasia (HPP) patients at The St. Louis Shriners Hospital for Children. In 2015, we published our findings in a paper entitled “Hypophosphatasia: Validation and expansion of the clinical nosology for children from 25 years of experience with 173 pediatric patients.” Here, we reported our TNSALP mutation findings along with clinical details from our pediatric patients diagnosed with Odonto, Childhood, or Infantile HPP. This detailed analysis allowed us to refine the nosology for HPP and separate the Childhood form into “Mild Childhood” and “Severe Childhood” forms. Our findings should improve understanding of HPP presentation, natural history, complications and prognosis. 

We continue to evaluate the role that TNSALP mutations play in women who are diagnosed with osteoporosis and treated with bisphosphonates, and subsequently exhibit an unusual fracture called “atypical subtrochanteric femoral fracture. These unusual fractures resemble those seen in Adult HPP. We proposed that some of these women may, in fact, have HPP instead of osteoporosis, and published the first case in 2012. We received a two-year grant from the National Institutes of Health to study this and reported initial findings at the 2013 American Society for Bone and Mineral Research meeting. We presented a second case of a woman diagnosed with “osteoporosis” showing a documented HPP mutation who suffered one of these unusual fractures. Our findings suggest that while TNSALP mutations may not have a major role in causing these unusual fractures, that it is important to distinguish the rare Adult HPP patients from the more common osteoporosis patient population. In 2016, I co-authored a paper entitled “Adult hypophosphatasia treated with teriparatide: Report of 2 patients and review of the literature.” Here we reported mixed results for teriparatide therapy for HPP but concluded that teriparatide shows some benefit for Adult HPP, which may be dependent on the number of TNSALP mutations (1 or 2) and the specific mutation(s) carried by the HPP patient.