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
José Luis Millán received his early training in clinical chemistry/biochemistry at the University of Buenos Aires, Argentina, and joined La Jolla Cancer Research Foundation, the predecessor of Sanford-Burnham Medical Research Institute, in 1977 as a trainee in Clinical enzymology. Dr. Millán then completed his Ph.D. studies at the University of Umeå, Sweden from 1981-1983 and after a period of postdoctoral training at the La Jolla Cancer Research Foundation he was appointed Assistant Professor in 1986 and promoted to Associate Professor in 1989 and to Full Professor in 1994 at the same institution. He held the Chair of Medical Genetics at the Department of Medical Biosciences, School of Medicine, Umeå University, Umeå, Sweden from 1995 to 2000. Dr. Millán is currently Professor at Sanford-Burnham Medical Research Institute, and he maintains adjunct affiliations with Umeå University and the Royal Academy of Medicine and Surgery, Murcia, Spain.
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
Inhibition of tissue-nonspecific alkaline phosphatase protects against medial arterial calcification and improved 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 2019 Sep 11 ;
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
Homoarginine Supplementation Prevents Left Ventricular Dilatation and Preserves Systolic Function in a Model of Coronary Artery Disease.
Rodionov RN, Begmatov H, Jarzebska N, Patel K, Mills MT, Ghani Z, Khakshour D, Tamboli P, Patel MN, Abdalla M, Assaf M, Bornstein SR, Millan JL, Bode-Böger SM, Martens-Lobenhoffer J, Weiss N, Savinova OV
J Am Heart Assoc 2019 Jul 16 ;8(14):e012486
Plaut JS, Strzelecka-Kiliszek A, Bozycki L, Pikula S, Buchet R, Mebarek S, Chadli M, Bolean M, Simao AMS, Ciancaglini P, Magrini A, Rosato N, Magne D, Girard-Egrot A, Farquharson C, Esener SC, Millan JL, Bottini M
Arch Biochem Biophys 2019 May 30 ;667:14-21
Is alkaline phosphatase biomimeticaly immobilized on titanium able to propagate the biomineralization process?
Andrade MAR, Derradi R, Simão AMS, Millán JL, Ramos AP, Ciancaglini P, Bolean M
Arch Biochem Biophys 2019 Mar 15 ;663:192-198