BONE-TARGETED ALKALINE PHOSPHATASE - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 421

phosphatase is unprecedent ed. This a pproach has gone
from concept design to the c linic (bench to beside) in 3
years. I a ttribute this to f our factors: (1) focused commit-
ment of Enobia Pharma to ENB-0040, the only drug in the
pi peli ne; (2) the ava il abil ity of a well-character ized HPP
a n i m a l m o d e l d evel o p e d i n o u r l a b o r a t o r y a n d o u r d e e p
understanding of HPP pathophysiology in mice; (3) superb
clinical ex pertise by Dr. Michael P. Whyt e, the world's
expert on HPP; and (4) last but not least, the dedicated
e ffo r t s o f a d vo c a cy g r o u p s 3,4 that helped inform pati ents,
their f amilies and physicians a bout progress made in
research and t he rapeutic fronts and also assisted in identi-
fying H PP patients s uitabl e f or i nclusion i n c linical t rials.

9. Van den Bos T, Handoko G, Niehof A, Ryan LM, Coburn SP,
Whyte MP, (2005) Cementum and dentin in hypophosphatasia.
J. Dent. Res. 84, 1021-1025.
10. Baumgartner-Sigl S, Haberlandt E, Mumm S, Scholl-Burgi S,
Sergi C, Ryan L, (2007) Pyridoxine-responsive seizures as the
first symptom of infantile hypophosphatasia caused by two
novel missense mutations (c.677T > C, p.M226T; c.1112C > T,
p.T371I) of the tissue-nonspecific alkaline phosphatase gene.
Bone 40, 1655-1661.
11. Waymire KG, Mahuren JD, Jaje JM, Guilarte TR, Coburn SP,
MacGregor GR. (1995) Mice lacking tissue non-specific alka-
line phosphatase die from seizures due to defective metabolism
of vitamin B-6. Nat. Genet. 11, 45-51.
12. Narisawa S, Fr € ohlander N, Mill an JL. (1997) Inactivation of
two mouse alkaline phosphatase genes and establishment of a
model of infantile hypophosphatasia. Dev. Dyn. 208, 432-446.
13. Narisawa S, Wennberg C, Mill an JL. (2001) Abnormal vitamin
B6 metabolism in alkaline phosphatase knock-out mice causes
multiple abnormalities, but not the impaired bone mineraliza-
tion. J. Pathol. 193, 125-133.
14. Fedde KN, Blair L, Silverstein J, Coburn SP, Ryan LM,
Weinstein RS, (1999) Alkaline phosphatase knock-out mice
recapitulate the metabolic and skeletal defects of infantile
hypophosphatasia. J. Bone Miner. Res. 14, 2015-2026.
15. Caswell AM, Whyte MP, Russell RG. (1991) Hypophospha-
tasia and the extracellular metabolism of inorganic pyro-
phosphate: clinical and laboratory aspects. Crit. Rev. Clin.
Lab. Sci. 28, 175-232.
16. Whyte MP, Valde s RJr, Ryan LM , McAlister W H. (1982)
Infantile hypopho s phatasia: enzyme replacement therapy by
i ntrave nous infusion of a lkal in e phos phatase-rich pl asma
from patient s with Paget's bone di sease. J. Pediatr. 101,
379-386 .
17. Whyte MP, McAlister WH, Patton LS, Magill HL, Fallon MD,
Lorentz WB, Jr, et al. (1984) Enzyme replacement therapy for
infantile hypophosphatasia attempted by intravenous infusions
of alkaline phosphatase-rich Paget plasma: results in three
additional patients. J. Pediatr. 105, 926-933.
18. Weninger M, Stinson RA, Plenk H, Jr, Bock P, Pollak A. (1989)
Biochemical and morphological effects of human hepatic
alkaline phosphatase in a neonate with hypophosphatasia.
Acta Paediatr. Scand. 360(Suppl), 154-160.
19. Whyte MP, Habib D, Coburn SP, Tecklenburg F, Ryan L, Fedde
KN, (1992) Failure of hyperphosphatasemia by intravenous
infusion of purified placental alkaline phosphatase (ALP) to
correct severe hypophosphatasia: evidence against a role for
circulating ALP in skeletal mineralization. J. Bone. Miner.
Res. 7, S155.
20. Whyte MP, Kurtzberg J, McAlister WH, Mumm S, Podgor-
nik MN, Coburn SP, et al. (2003) Marrow cell transplanta-
tion for infantile hypophosphatasia. J.Bone.Miner.Res.18,
624-636.
21. Cahill RA, Wenkert D, Perlman SA, Steele A, Coburn SP,
McAlister WH, et al. (2007) Infantile hypophosphatasia:
transplantation therapy trial using bone fragments and cultured
osteoblasts. J Clin. Endocrinol. Metabol. 92, 2923-2930.

ACKNOWL EDGMEN TS

I thank Dr. Ph ilippe Crine, Ph.D., Vice Presid ent and Chief
Scientific Offi cer of Enobia Pharma Inc. for generousl y
sharing data and com pany reports with me and for his
comments on this chapter.

REFER ENCES

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3 http://www.hypophosphatasie.com
4 http://www.softbones.org