José Luis Millán's Research Focus
The Millán laboratory works on understanding the mechanisms that control normal skeletal and dental mineralization and elucidating the pathophysiological abnormalities that lead to heritable soft bones conditions such as Hypophosphatasia (HPP) and to soft-tissue calcification, including vascular calcification, that is a hallmark feature in patients affected by a variety of rare genetic diseases as well as in chronic kidney disease. Dr. Millan’s research has already contributed to the implementation of a novel therapy for HPP, a genetic disease caused by deficiency in tissue-nonspecific alkaline phosphatase (TNAP) function, that leads to accumulation in the extracellular space of inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. HPP is characterized by defective mineralization of bones (rickets or osteomalacia), and teeth that display a lack of acellular cementum, hypomineralized dentin and enamel, and periodontal defects. Dr. Millán’s team has demonstrated the effectiveness of enzyme replacement therapy using mineral-targeted recombinant TNAP (asfotase alfa) to prevent the skeletal and dental defects in the TNAP knockout mouse model of infantile HPP. This therapy was approved in 2015 for the treatment of patients with pediatric-onset HPP.
Current efforts in Dr. Millán’s laboratory are focused on clarifying aspects of HPP disease whose pathophysiology are not yet well understood, such as the premature fusion of skull bones (craniosynostosis) and calcification of the kidney parenchyma (nephrocalcinosis). Dr. Millán’s group has also identified key pathophysiological changes that lead to calcification of the arteries in animal models of generalized arterial calcification of infancy and related genetic diseases as well as in animal models of chronic kidney disease. His group, in collaboration with scientists at the Conrad Prebys Center for Chemical Genomics at SBP, has developed proprietary compounds able to ameliorate the soft-tissue calcification in these conditions and clinical trials are now underway using these first-in-class compounds.
José Luis Millán's Bio
After receiving his early training in clinical chemistry/biochemistry at the University of Buenos Aires, Argentina, Dr. Millán first joined the La Jolla Cancer Research Foundation (LJCRF) in 1977, the predecessor of SBP, as a trainee in clinical enzymology. He completed his Ph.D. studies in Medical Biochemistry at the University of Umeå, Sweden and after post-doctoral stints in Copenhagen and LJCRF he was appointed to the faculty at SBP in 1986. He served as Professor of Medical Genetics in the Department of Medical Biosciences at his alma mater, Umeå University, Sweden, from 1995-2000. He was appointed Sanford Investigator at the Sanford Children’s Health Research Center at SBP in 2008.
Honors and Recognition
- 1992 - Honorary title of AcadémicoCorresponsal at the Royal Academy of Medicine and Surgery, Murcia, Spain.
- 2001 - Gold Medal of the Royal Academy of Medicine and Surgery, Murcia, Spain
- ASBMR 2018 Lawrence G. Raisz Award for Pre-clinical Research.
Member - Scientific Advisory Board, Soft Bones
In vivo overexpression of tissue-nonspecific alkaline phosphatase increases skeletal mineralization and affects the phosphorylation status of osteopontin.
Narisawa S, Yadav MC, Millán JL
J Bone Miner Res 2013 Jul ;28(7):1587-98
Tissue-nonspecific Alkaline Phosphatase Regulates Purinergic Transmission in the Central Nervous System During Development and Disease.
Sebastián-Serrano Á, de Diego-García L, Martínez-Frailes C, Ávila J, Zimmermann H, Millán JL, Miras-Portugal MT, Díaz-Hernández M
Comput Struct Biotechnol J 2015 ;13:95-100
Bravo Y, Teriete P, Dhanya RP, Dahl R, Lee PS, Kiffer-Moreira T, Ganji SR, Sergienko E, Smith LH, Farquharson C, Millán JL, Cosford ND
Bioorg Med Chem Lett 2014 Sep 1 ;24(17):4308-11
Systemic inhibition of tissue-nonspecific alkaline phosphatase alters the brain-immune axis in experimental sepsis.
Brichacek AL, Benkovic SA, Chakraborty S, Nwafor DC, Wang W, Jun S, Dakhlallah D, Geldenhuys WJ, Pinkerton AB, Millán JL, Brown CM
Sci Rep 2019 Dec 11 ;9(1):18788
Loss of tissue-nonspecific alkaline phosphatase (TNAP) enzyme activity in cerebral microvessels is coupled to persistent neuroinflammation and behavioral deficits in late sepsis.
Nwafor DC, Chakraborty S, Brichacek AL, Jun S, Gambill CA, Wang W, Engler-Chiurazzi EB, Dakhlallah D, Pinkerton AB, Millán JL, Benkovic SA, Brown CM
Brain Behav Immun 2019 Nov 25 ;
Cholesterol Regulates the Incorporation and Catalytic Activity of Tissue-Nonspecific Alkaline Phosphatase in DPPC Monolayers.
Derradi R, Bolean M, Simão AMS, Caseli L, Millán JL, Bottini M, Ciancaglini P, Ramos AP
Langmuir 2019 Nov 26 ;35(47):15232-15241
Inhibition of tissue-nonspecific alkaline phosphatase protects against medial arterial calcification and improves survival probability in the CKD-MBD mouse model.
Tani T, Fujiwara M, Orimo H, Shimizu A, Narisawa S, Pinkerton AB, Millán JL, Tsuruoka S
J Pathol 2020 Jan ;250(1):30-41
Dillon S, Staines KA, Millán JL, Farquharson C
JBMR Plus 2019 Jul ;3(7):e10202
Patel JJ, Bourne LE, Millán JL, Arnett TR, MacRae VE, Wheeler-Jones CPD, Orriss IR
Purinergic Signal 2019 Sep ;15(3):315-326