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Abstract

A number of mucopolysaccharidosis type VII (MPS VII) mouse models with different levels of residual enzyme activity have been created replicating the range of clinical phenotypes observed in human MPS VII patients. In this study, a lentivirus encoding murine β-glucuronidase was administered intravenously at birth to both the severe (Gus^mps/mps strain) and attenuated (Gus^tm(L175F)Sly strain) mouse models of MPS VII. Circulating enzyme levels were normalized in the Gus^mps/mps mice and were 3.5-fold higher than normal in the Gus^tm(L175F)Sly mouse 12 and 18 months after administration. Tissue β-glucuronidase activity increased over untreated levels in all tissues evaluated in both strains at 12 months, and the elevated level was maintained in Gus^tm(L175F)Sly tissues at 18 months. These elevated enzyme levels reduced glycosaminoglycan storage in the liver, spleen, kidney, and heart in both models. Bone mineral volume decreased toward normal in both models after 12 months of therapy and after 18 months in the Gus^tm(L175F)Sly mouse. Open-field exploration was improved in 18-month-old treated Gus^tm(L175F)Sly mice, while spatial learning improved in both 12- and 18-month-old treated Gus^tm(L175F)Sly mice. Overall, neonatal administration of lentiviral gene therapy resulted in sustained enzyme expression for up to 18 months in murine models of MPS VII. Significant improvements in biochemistry and enzymology as well as functional improvement of bone and behavior deficits in the Gus^tm(L175F)Sly model were observed. Therapy significantly increased the lifespan of Gus^mps/mps mice, with 12 months being the longest reported lentiviral treatment for this strain. It is important to assess the long-term outcome on enzyme levels and effect on pathology for lentiviral gene therapy to be a potential therapy for MPS patients.

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References

Anson

D.S.

, McIntyre

, Thomas

, et al. (2007). Lentiviral-mediated gene correction of mucopolysaccharidosis type IIIA. Genet. Vaccines Ther., 5, 1.

Bernsen

P.L.

, Wevers

R.A.

, Gabreels

F.J.

, et al. (1987). Phenotypic expression in mucopolysaccharidosis VII. J. Neurol. Neurosurg. Psychiatry, 50, 699–703.

Bielicki

, McIntyre

, and Anson

D.S.

(2010). Comparison of ventricular and intravenous lentiviral-mediated gene therapy for murine MPS VII. Mol. Genet. Metab., 101, 370–382.

Birkenmeier

E.H.

, Davisson

M.T.

, Beamer

W.G.

, et al. (1989). Murine mucopolysaccharidosis type VII. Characterization of a mouse with beta-glucuronidase deficiency. J. Clin. Invest., 83, 1258–1266.

Bosch

, Perret

, Desmaris

, et al. (2000). Reversal of pathology in the entire brain of mucopolysaccharidosis type VII mice after lentivirus-mediated gene transfer. Hum. Gene Ther., 11, 1139–1150.

Buchmann

, Bauer-Hofmann

, Mahr

, et al. (1991). Mutational activation of the c-Ha-ras gene in liver tumors of different rodent strains: correlation with susceptibility to hepatocarcinogenesis. Proc. Natl. Acad. Sci. USA, 88, 911–915.

Copreni

, Castellani

, Palmieri

, et al. (2008). Involvement of glycosaminoglycans in vesicular stomatitis virus G glycoprotein pseudotyped lentiviral vector-mediated gene transfer into airway epithelial cells. J. Gene Med., 10, 1294–1302.

Cotugno

, Tessitore

, Capalbo

, et al. (2010). Different serum enzyme levels are required to rescue the various systemic features of the mucopolysaccharidoses. Hum. Gene Ther., 21, 555–569.

Daly

T.M.

, Okuyama

, Vogler

, et al. (1999). Neonatal intramuscular injection with recombinant adeno-associated virus results in prolonged beta-glucuronidase expression in situ and correction of liver pathology in mucopolysaccharidosis type VII mice. Hum. Gene Ther., 10, 85–94.

10.

Daly

T.M.

, Ohlemiller

K.K.

, Roberts

M.S.

, et al. (2001). Prevention of systemic clinical disease in MPS VII mice following AAV-mediated neonatal gene transfer. Gene Ther., 8, 1291–1298.

11.

Donsante

, Miller

D.G.

, Li

, et al. (2007). AAV vector integration sites in mouse hepatocellular carcinoma. Science, 317, 477.

12.

Donsante

, Vogler

, Muzyczka

, et al. (2001). Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors. Gene Ther., 8, 1343–1346.

13.

Elliger

S.S.

, Elliger

C.A.

, Lang

, and Watson

G.L.

(2002). Enhanced secretion and uptake of beta-glucuronidase improves adeno-associated viral-mediated gene therapy of mucopolysaccharidosis type VII mice. Mol. Ther., 5, 617–626.

14.

Folch

, Lees

, and Sloane Stanley

G.H.

(1957). A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem., 226, 497–509.

15.

Gitzelmann

, Bosshard

N.U.

, Superti-Furga

, et al. (1994). Feline mucopolysaccharidosis VII due to beta-glucuronidase deficiency. Vet. Pathol., 31, 435–443.

16.

Glatt

, Canalis

, Stadmeyer

, and Bouxsein

M.L.

(2007). Age-related changes in trabecular architecture differ in female and male C57BL/6J mice. J. Bone Miner. Res., 22, 1197–1207.

17.

Guibinga

G.H.

, Miyanohara

, Esko

J.D.

, and Friedmann

(2002). Cell surface heparan sulfate is a receptor for attachment of envelope protein-free retrovirus-like particles and VSV-G pseudotyped MLV-derived retrovirus vectors to target cells. Mol. Ther., 5, 538–546.

18.

Hakomori

S.I.

, and Siddiqui

(1974). Isolation and characterization of glycosphingolipid from animal cells and their membranes. Methods Enzymol., 32, 345–367.

19.

Haskins

M.E.

, Desnick

R.J.

, DiFerrante

, et al. (1984). Beta-glucuronidase deficiency in a dog: a model of human mucopolysaccharidosis VII. Pediatr. Res., 18, 980–984.

20.

Kahn

, Gibbons

, Perkins

, and Gazit

(1995). Age-related bone loss. A hypothesis and initial assessment in mice. Clin. Orthop. Relat. Res. (313), 69–75.

21.

Kobayashi

, Carbonaro

, Pepper

, et al. (2005). Neonatal gene therapy of MPS I mice by intravenous injection of a lentiviral vector. Mol. Ther., 11, 776–789.

22.

Koldej

, Cmielewski

, Stocker

, et al. (2005). Optimisation of a multipartite human immunodeficiency virus based vector system; control of virus infectivity and large-scale production. J. Gene Med., 7, 1390–1399.

23.

Leaback

D.H.

, and Walker

P.G.

(1961). Studies on glucosaminidase. 4. The fluorimetric assay of N-acetyl-beta-glucosaminidase. Biochem. J., 78, 151–156.

24.

Liu

, Chen

Y.H.

, He

, et al. (2007). Adeno-associated virus type 5 reduces learning deficits and restores glutamate receptor subunit levels in MPS VII mice CNS. Mol. Ther., 15, 242–247.

25.

Lowenstein

P.R.

, and Enquist

L.W.

(1996). Protocols for Gene Transfer in Neuroscience: Towards Gene Therapy of Neurological Disorders (Wiley, John & Sons, Inc., New York, NY).

26.

Macsai

C.E.

, Derrick-Roberts

A.L.

, Ding

, et al. (2012). Skeletal response to lentiviral mediated gene therapy in a mouse model of MPS VII. Mol. Genet. Metab., 106, 202–213.

27.

Mango

R.L.

, Xu

, Sands

M.S.

, et al. (2004). Neonatal retroviral vector-mediated hepatic gene therapy reduces bone, joint, and cartilage disease in mucopolysaccharidosis VII mice and dogs. Mol. Genet. Metab., 82, 4–19.

28.

Metcalf

J.A.

, Zhang

, Hilton

M.J.

, et al. (2009). Mechanism of shortened bones in mucopolysaccharidosis VII. Mol. Genet. Metab., 97, 202–211.

29.

Negishi

, Chen

, McCarty

D.M.

, et al. (2004). Analysis of the interaction between adeno-associated virus and heparan sulfate using atomic force microscopy. Glycobiology, 14, 969–977.

30.

Neufeld

E.F.

, and Muenzer

(2001). The mucopolysaccharidoses. In The Metabolic and Molecular Bases of Inherited Disease. Scriver

C.R.

, Beaudet

A.L.

, Sly

W.S.

, and Valle

, eds. (McGraw-Hill Companies, Inc., New York, NY) pp. 3421–3452.

31.

Roberts

A.L.

, Thomas

B.J.

, Wilkinson

A.S.

, et al. (2006). Inhibition of glycosaminoglycan synthesis using rhodamine B in a mouse model of mucopolysaccharidosis type IIIA. Pediatr. Res., 60, 309–314.

32.

Roberts

A.L.

, Rees

M.H.

, Klebe

, et al. (2007). Improvement in behaviour after substrate deprivation therapy with rhodamine B in a mouse model of MPS IIIA. Mol. Genet. Metab., 92, 115–121.

33.

Ross

C.J.

, Bastedo

, Maier

S.A.

, et al. (2000). Treatment of a lysosomal storage disease, mucopolysaccharidosis VII, with microencapsulated recombinant cells. Hum. Gene Ther., 11, 2117–2127.

34.

Sands

M.S.

, and Birkenmeier

E.H.

(1993). A single-base-pair deletion in the beta-glucuronidase gene accounts for the phenotype of murine mucopolysaccharidosis type VII. Proc. Natl. Acad. Sci. USA, 90, 6567–6571.

35.

Schwartz

, Silva

L.R.

, Leistner

, et al. (2003). Mucopolysaccharidosis VII: clinical, biochemical and molecular investigation of a Brazilian family. Clin. Genet., 64, 172–175.

36.

Sewell

A.C.

, Gehler

, Mittermaier

, and Meyer

(1982). Mucopolysaccharidosis type VII (beta-glucuronidase deficiency): a report of a new case and a survey of those in the literature. Clin. Genet., 21, 366–373.

37.

Sferra

T.J.

, Qu

, McNeely

, et al. (2000). Recombinant adeno-associated virus-mediated correction of lysosomal storage within the central nervous system of the adult mucopolysaccharidosis type VII mouse. Hum. Gene Ther., 11, 507–519.

38.

Silverstein Dombrowski

D.C.

, Carmichael

K.P.

, Wang

, et al. (2004). Mucopolysaccharidosis type VII in a German Shepherd dog. J. Am. Vet. Med. Assoc., 224, 532–533, 553–557.

39.

Sly

W.S.

, Quinton

B.A.

, McAlister

W.H.

, and Rimoin

D.L.

(1973). Beta glucuronidase deficiency: report of clinical, radiologic, and biochemical features of a new mucopolysaccharidosis. J. Pediatr., 82, 249–257.

40.

Sly

W.S.

, Vogler

, Grubb

J.H.

, et al. (2001). Active site mutant transgene confers tolerance to human beta-glucuronidase without affecting the phenotype of MPS VII mice. Proc. Natl. Acad. Sci. USA, 98, 2205–2210.

41.

Tomatsu

, Orii

K.O.

, Vogler

, et al. (2002). Missense models [Gustm(E536A)Sly, Gustm(E536Q)Sly, and Gustm(L175F)Sly] of murine mucopolysaccharidosis type VII produced by targeted mutagenesis. Proc. Natl. Acad. Sci. USA, 99, 14982–14987.

42.

Tomatsu

, Montano

A.M.

, Dung

V.C.

, et al. (2009). Mutations and polymorphisms in GUSB gene in mucopolysaccharidosis VII (Sly Syndrome). Hum. Mutat., 30, 511–519.

43.

B.M.

, Tomatsu

, Fukuda

, et al. (1994). Overexpression rescues the mutant phenotype of L176F mutation causing beta-glucuronidase deficiency mucopolysaccharidosis in two Mennonite siblings. J. Biol. Chem., 269, 23681–23688.

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Lentiviral-Mediated Gene Therapy Results in Sustained Expression of β-Glucuronidase for up to 12 Months in the Gus mps/mps and up to 18 Months in the Gus tm(L175F)Sly Mouse Models of Mucopolysaccharidosis Type VII

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