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 in patients affected by a variety of rare genetic diseases as well as in chronic kidney disease. Dr. Millán’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 collaboration with Professor Miyake’s group in Japan (https://www.nms-gt.org/en/members), focus on developing gene therapy as an alternative approach to treat HPP. 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, pseudoxanthoma elasticum 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 Sanford Burnham Prebys, 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 small molecule inhibitors.
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 Sanford Burnham Prebys, 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 Sanford Burnham Prebys in 2008.
Honors and Recognition
2018: ASBMR Lawrence G. Raisz Award for Pre-clinical Research.
2001: Gold Medal of the Royal Academy of Medicine and Surgery, Murcia, Spain
1992: Honorary title of AcadémicoCorresponsal at the Royal Academy of Medicine and Surgery, Murcia, Spain.
Member, Scientific Advisory Board, Soft Bones
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
Amadeu de Oliveira F, Narisawa S, Bottini M, Millán JL
J Bone Miner Res 2020 Sep ;35(9):1765-1771
Gene Therapy Using Adeno-Associated Virus Serotype 8 Encoding TNAP-D(10) Improves the Skeletal and Dentoalveolar Phenotypes in Alpl(-/-) Mice.
Kinoshita Y, Mohamed FF, Amadeu de Oliveira F, Narisawa S, Miyake K, Foster BL, Millán JL
J Bone Miner Res 2021 Sep ;36(9):1835-1849
Evidence that pyrophosphate acts as an extracellular signalling molecule to exert direct functional effects in primary cultures of osteoblasts and osteoclasts.
Bourne LE, Davies BK, Millan JL, Arnett TR, Wheeler-Jones CPD, Keen JAC, Roberts SJ, Orriss IR
Bone 2023 Nov ;176:116868
Mohamed FF, Amadeu de Oliveira F, Kinoshita Y, Yalamanchili RR, Eltilib LA, Andras NL, Narisawa S, Tani T, Chu EY, Millán JL, Foster BL
J Bone Miner Res 2023 Aug ;38(8):1192-1207
Spatial Lipidomic Profiling of Mouse Joint Tissue Demonstrates the Essential Role of PHOSPHO1 in Growth Plate Homeostasis.
Tzvetkov J, Stephen LA, Dillon S, Millan JL, Roelofs AJ, De Bari C, Farquharson C, Larson T, Genever P
J Bone Miner Res 2023 May ;38(5):792-807
Weighing the Evidence for the Roles of Plasma Versus Local Pyrophosphate in Ectopic Calcification Disorders.
Ralph D, Levine M, Millán JL, Uitto J, Li Q
J Bone Miner Res 2023 Apr ;38(4):457-463
Gene Therapy Using Recombinant AAV Type 8 Vector Encoding TNAP-D(10) Improves the Skeletal Phenotypes in Murine Models of Osteomalacia.
Amadeu de Oliveira F, Mohamed FF, Kinoshita Y, Narisawa S, Farquharson C, Miyake K, Foster BL, Millan JL
JBMR Plus 2023 Jan ;7(1):e10709
Increased PHOSPHO1 and alkaline phosphatase expression during the anabolic bone response to intermittent parathyroid hormone delivery.
Houston DA, Stephen LA, Jayash SN, Myers K, Little K, Hopkinson M, Pitsillides AA, MacRae VE, Millan JL, Staines KA, Farquharson C
Cell Biochem Funct 2023 Mar ;41(2):189-201