Year: 2018
Type: conference-abstract
Abstract: From June 8 to 10, 2018, in Chicago, IL, USA, a multinational group of 50 clinicians, clinical investigators, and basic scientists gathered with other interested individuals to convene the First Scientific Meeting of the Soft Bones Foundation. They reviewed current understanding and uncertainties concerning hypophosphatasia (HPP) and planned work necessary to improve the lives of people with this inborn error of metabolism. The importance for such a meeting was perceived by Ms. Deborah Fowler, President and Founder of the Soft Bones Foundation, and was brought to success with the help of Ms. Denise Goodbar and Ms. Charlene Waldman and support from Alexion Pharmaceuticals, PANTHERx Specialty Pharmacy, and Charles River Laboratories, Inc. Session moderators Matthew Drake, MD, PhD, Eric Rush, MD, Frank Rauch, MD, Mark Nunes, MD, Kathryn Dahir, MD, Craig Langman, MD, and Susan Ott, MD, expertly kept to time the considerable enthusiasm of all attendees. Graham Russell, MD, PhD, gave a historical review of inorganic pyrophosphate, its action as an inhibitor of mineralization, excess in HPP, and early experiences following its modification to become the bisphosphonates. Michael Whyte, MD, described the discovery in 1923 of alkaline phosphatase (ALP), the first report in 1948 of HPP, and the many important lessons from investigation of patients, including major insight concerning the pathogenesis of the defective hard tissue mineralization leading to tooth loss and rickets during childhood and osteomalacia during adult life as well as identification of its etiology. The expanded clinical nosology of HPP was validated after using the now delineated clinical, biochemical, radiological, and histopathological features of this metabolic bone disease. Stephen Coburn, PhD, discussed the derangement of vitamin B6 metabolism leading to extracellular accumulation of the deficient tissue nonspecific ALP isoenzyme (TNSALP) substrates including pyridoxal 5′ phosphate, and the pathogenesis of the vitamin B6 dependent seizures. Jose Luis Millan, PhD, reviewed the importance of mouse models for HPP, including their role in preclinical studies of asfotase alfa (AA) enzyme replacement therapy for HPP, and investigation of other molecules that regulate skeletal mineralization. Larry Suva, PhD, described the recent development of the first large animal Model (ie, sheep) for HPP, and the early findings concerning the clinical and biochemical phenotype. Deborah Kraków, MD, discussed the considerable uncertainties with prenatal radiological imaging of HPP, and Deborah Wenkert, MD, defined and reviewed the management of the not uncommon “benign prenatal” form. Steven Mumm, PhD, provided an overview concerning the Mendelian inheritance of HPP, and what can be said concerning genotype/phenotype correlations. Treatment for HPP now includes the benefits from enzyme replacement using AA (Strensiq™), approved multinationally in 2015 typically for pediatric onset HPP. Philippe Crine, PhD, reviewed the recombinant DNA structuring of AA as a TNSALP targeted to hydroxyapatite. Jill Simmons, MD, described the improvements in skeletal mineralization, respiratory and motor function, and growth observed during AA treatment studied initially for the life threatening perinatal and infantile forms of HPP and followed to 7 years of therapy. Nicholas Bishop, MD, and Vrinda Saraff, MD, reported experience with such patients in the United Kingdom. Keiichi Ozono, MD, PhD, presented the Japanese experience with severe pediatric HPP. Then, Gary Gottesman, MD, provided an overview concerning AA treatment for older children debilitated by HPP, including the problems as well as the benefits. Donna Griffin, PT, PCS, reported how a modification of the Performance Oriented Mobility Assessment gait (mPOMA G) could assess in real time baseline and treatment responses of children with HPP. Lothar Seefried, MD, discussed the orthopedic complications and management of adults with HPP, including experience with AA treatment. The broad range of HPP severity encountered in this age group was reviewed by Peter Tebben, MD, and Frederick Singer, MD, discussed the difficulties with diagnosis and treatment of these individuals. Priya Krishnani, MD, outlined the importance of functional testing of adults with HPP, and what improvements have been observed with AA treatment. Pauline Camacho, MD, discussed “off label” use of parathyroid hormone given to adults with HPP. Mark Rallo, OD, discussed occurrences of ectopic calcification on conjunctiva naturally in HPP, and perhaps increased with AA treatment but largely microscopic and asymptomatic. Timothy Wright, MS, DDS, reviewed oral and craniofacial issues of HPP, and emphasized how much more must be learned about these complications, especially in adults. Brian Foster, PhD, discussed the importance of TNSALP in dentoalveolar tissue formation, and the consequences of TNSALP deficiency in HPP. Clifford Rosen, MD, reviewed early work concerning a potential role for ALP in fat metabolism, including fat accumulation at sites of AA injection in patients with HPP. Isabel Orriss, PhD, provided an overview of skeletal mineralization controlled by TNSALP and pyrophosphate, and other factors. Progress reports, summarized in their abstracts compiled herein, were provided by the past recipients of research awards from the Soft Bones Foundation: Steven Mumm, PhD, Luke Mortensen, PhD, Brian Foster, PhD, and Katheryn Dahir, MD. Finally, means to advance the treatment or to cure HPP, including by gene editing, ALP transfection, and mesenchymal stem cell therapy, were discussed by José Luis Millan, PhD, and Luke Mortensen, PhD. Here are the abstracts from the meeting. We are grateful to JBMR Plus for publishing them, so that they can be accessed worldwide. Michael P. Whyte, MD Chair, Scientific Advisory Board Soft Bones Foundation Boonton, NJ, USA https://www.softbones.org/ The identification of inorganic pyrophosphate (PPi) as a key regulator of biological calcification can be traced back to the 1960s, starting with the work of Fleisch and colleagues.(1) Hypophosphatasia (HPP) was identified as the first of the pyrophosphate diseases.(2,3) This established the notion that ALP was an important enzyme in regulating extracellular pyrophosphate levels. In the early years, we established that pyrophosphate appearing in blood and was in with that a in the extracellular a that could be by phosphate, at that time as a potential treatment for are many enzyme in that of pyrophosphate now that pyrophosphate in and at cell by the of and The role of the in the of cell in have been in the pathogenesis of to use pyrophosphate or to calcification were by its in the and its to be the was these that studies of as pyrophosphate The discovery of the biological of especially as of bone to their and current use as the major for the treatment of bone including bone and Russell, of pyrophosphate on and its in Russell, of inorganic pyrophosphate in Russell, pyrophosphate in in and in patients with and other of Russell, The of pyrophosphate in of Orriss, Russell, a key inhibitor of Russell, the first Michael for and for USA of and of of USA hypophosphatasia (HPP) the severity range of all skeletal and was the to a of what we about the of ALP from studies of HPP In to the rickets and of an and skeletal ALP tooth loss from the pathogenesis to hard in HPP of and inorganic pyrophosphate (PPi) and pyridoxal 5′ in blood to be a for of of ALP from HPP HPP an inborn error of the tissue nonspecific isoenzyme of ALP that all HPP patients or defective (TNSALP) This after its discovery in that ALP in skeletal mineralization. The metabolism of vitamin B6 TNSALP a cell was to and other to cell and especially severe HPP by by in the The for the defective mineralization was to be in HPP but to after of and accumulation in HPP the of ALP their the ALP in a The of HPP that TNSALP of inorganic the severity range of HPP by identified the of In asfotase alfa treatment for HPP patients the role in in Stephen USA of tissue nonspecific alkaline phosphatase (TNSALP) in hypophosphatasia (HPP) with increased of pyridoxal 5′ in The of pyridoxal and in HPP, from increased of vitamin the of all studies in that the the of with The life of a of in to not by the in of HPP of ALP by a in after TNSALP an to be a phosphatase the a of metabolism of vitamin B6 in with HPP other dependent in and from the from In these was more in in HPP patients, and tissue B6 are in the for ALP use and of inorganic ALP about HPP of the vitamin B6 in the with in We have not on in HPP. We are a of vitamin B6 metabolism that we vitamin B6 metabolism in and José Luis USA Hypophosphatasia (HPP) the that from gene leading to deficient of the tissue nonspecific alkaline phosphatase HPP features rickets or osteomalacia and early loss of infantile HPP well and have to the role of in the of HPP. The mouse studies have that the skeletal and of HPP are by the accumulation of extracellular inorganic pyrophosphate a of and a mineralization mineralization inhibitor the of extracellular mineralization. HPP patients, as well as of the from severe that a The are by of pyridoxal phosphate, of that a in the of in the but in the of the leading to seizures. this provided the for the current for pediatric onset HPP using recombinant targeted for enzyme replacement that the and the skeletal and of the The of other features of HPP and are not from the mouse models that these be at in by in the as a of deficient of leading to that cell and tissue Larry Brian Mark Charles of and of and USA of of The USA of of and USA The of a for to the of in or perhaps more to animal models of bone in the bone more that observed in an animal of a the the the and to be and be the use of models been by the of mouse and their animal the to the the and the of a range of of the have with that the by such as and and their the and of a bone hypophosphatasia we as a animal gene a was the tissue nonspecific alkaline phosphatase (TNSALP) gene the first large animal of HPP. to HPP have alkaline phosphatase bone and with mineralization observed in HPP that are of and are of including and and and in and of bone in HPP HPP. and in HPP to HPP bone and of of and tooth development and and of and such as and all of are the of investigation in Deborah of and of at the of USA of of at USA of of at USA The of to in the are the skeletal for of or of all The skeletal are a group of more many of in the prenatal hypophosphatasia (HPP) can be as a or The prenatal of HPP perinatal and from in the gene that tissue nonspecific alkaline phosphatase are by in with of skeletal findings in the perinatal of HPP mineralization of the and and the of the with mineralization and mineralization of the of the and in are prenatal findings can with severe forms of bone and other bone skeletal of of at or to and of HPP, more Deborah USA for USA In we of prenatal hypophosphatasia of pediatric HPP and reviewed patients typically improve during the ALP and ALP substrates in a as well as after The clinical and biochemical are with a on the age and severity of their first clinical We that the following inheritance of and or in the HPP in skeletal in of mineralization was and including with perinatal and in the and of patients a In or of of and in a age of a skeletal at of the in with mineralization at to with and HPP. with HPP not have in HPP but for HPP. 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Whyte, Simmons, Bishop, and with Hypophosphatasia with 7 and were largely presented at the Michael and Nicholas on of the for and for USA of and of of at USA Alexion Pharmaceuticals, USA Vrinda of and and of the for Hypophosphatasia with from and The first with asfotase alfa was in in the for of treatment that the was to for the for the treatment of in the studies of asfotase alfa in and patients from and the the and patients in from the and a of asfotase alfa as of the use In patients with infantile or perinatal onset HPP have been with asfotase alfa treatment in the The lessons learned have been clinical and diagnosis and treatment in important to respiratory with respiratory problems a in with other severe bone in such as and to respiratory to be more and early treatment HPP patients to of to the development of in to and improve mineralization. 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The for this are that adults have or and and that to alkaline phosphatase levels. that alkaline phosphatase be a in a large of other of replacement therapy, or and therapy for HPP from these of an pyridoxal 5′ to be of this not been in large of patients with these testing be the means of HPP, but a not the of disease. The to the of the bone an bone after from HPP. the for treatment of HPP in children and in adults with to the are to what treatment be an asfotase in children and in adults. studies that the in but not all of the have been benefits in HPP The what to with an have bone This clinical are clinical of replacement in early be more to have skeletal problems to increased bone as well as mineralization. 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Brian of of The USA of of The USA USA of and USA of and of and USA for and for USA of and of of at USA nonspecific alkaline phosphatase a enzyme for skeletal and mineralization, of the mineralization inorganic of in the the gene hypophosphatasia an error of metabolism with and bone HPP the tooth loss to are reported for and these on in including that HPP with biochemical, or now an enzyme replacement therapy approved in the United and of on dentoalveolar to these studies of from individuals with clinical forms of HPP were in with development of mouse models of HPP for were from a large of HPP clinical and severe and have been and were by and and to from a HPP mouse models were by a to and and and were by blood and studies on from a with HPP identified in and a in with in at ALP in and skeletal and mineralization HPP including defective formation, mineralization, and accumulation at bone of tissue mineralization by HPP of the for and models for and of Clifford USA HPP by mineralization, bone and to loss of in tissue nonspecific alkaline (TNSALP) of asfotase alfa to treatment in the fat at injection a The of this to asfotase alfa not been could potential a to that and from the as fat and alkaline phosphatase during and of alkaline phosphatase in by and the of TNSALP and can in of the during of ALP by are that the of in are to alkaline phosphatase and be we that in at of was a in bone tissue This in been in bone from individuals with HPP. the functional of TNSALP in cell we in tissue using the fat and in early mesenchymal in the using the from these be presented and a be in and In the this an important mesenchymal and cell to for to asfotase alfa treatment. Isabel of the past years, become that extracellular an important role in bone by and bone the extracellular in a controlled can in an to work that extracellular and are important of bone mineralization. to an of mineralization and alkaline phosphatase and are this on mineralization studies and work using that these are in by the and 7 many extracellular The of by the and pyrophosphate the inhibitor of mineralization. In with this role regulating mineralization, skeletal and tissue can of in and that the of on bone mineralization are in of a major of extracellular in bone and that the of have been now that
Source: JBMR Plus
DOI: 10.1002/jbm4.10082
Authors: R Graham, G Russell, Michael P Whyte, Stephen Coburn, Karen Ericson, Dennis Mahuren, Douglas Townsend, José Luis Millán, Larry Suva, Diarra K Williams, Carlos Pinzón, Shannon Huggins, Jane H Pryor, Alyssa Falck, Forrest Herman, James Oldeschulte, Brian L Foster, Mark E Westhusin, Charles R Long, Dana Gaddy, Deborah Krakow, Deborah Wenkert, Steven Mumm, Philippe Crine, Jill Simmons, Nick Bishop, Vrinda Saraff, Keiichi Ozono, Taichi Kitaoka, Takuo Kubota, Gary S Gottesman, Donna Griffin, Erica Morrison, Jennifer Wallenberg, Vinieth N. Bijanki, Fan Zhang, Lothar Seefried, Peter Tebben, Frederick R Singer, Priya S Kishnani, Pauline M Camacho, Mark S Rallo, Tim Wright, Brian Foster, MB Chavez, K Kramer, TN Kolli, MH Tan, S Narisawa, D Gaddy, LJ Suva, MP Whyte, JL Millan, Clifford Rosen, Isabel R Orriss, José Luis Millán, Luke J Mortensen
Institutions: University of Oxford, University of Sheffield, Barnes-Jewish Hospital, Washington University in St. Louis, Shriners Hospitals for Children - St. Louis, Indiana University – Purdue University Fort Wayne, Sanford Burnham Prebys Medical Discovery Institute, Texas A&M University, The Ohio State University, University of California, Los Angeles, Vanderbilt University Medical Center, Sheffield Children's Hospital, Birmingham Women's Hospital, The University of Osaka, University of Würzburg, Mayo Clinic, Saint John's Health Center, Duke Medical Center, Loyola University Medical Center, Loyola University Chicago, St. Louis Children's Hospital, Washington University Medical Center, University of North Carolina at Chapel Hill, Maine Medical Center Research Institute, Royal Veterinary College, University of Georgia
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,888
OpenAlex ID: W4255038934