MPS I |
non-viral vectors |
Hydrodinamic injection, subcutaneous |
mice, adult |
variable |
Yes |
Yes |
Use of Sleeping Beauty transposon, DNA minicircle and microencapsulated cells |
(Aronovich et al., 2009Aronovich EL, Bell JB, Khan SA, Belur LR, Gunther R, Koniar B, Schachern PA, Parker JB, Carlson CS, Whitley CB et al. (2009) Systemic correction of storage disease in MPS I NOD/SCID mice using the sleeping beauty transposon system. Mol Ther 17:1136-1144.; Lizzi Lagranha et al., 2017Lizzi Lagranha V, Zambiasi Martinelli B, Baldo G, Avila Testa G, Giacomet de Carvalho T, Giugliani R and Matte U (2017) Subcutaneous implantation of microencapsulated cells overexpressing alpha-L-iduronidase for mucopolysaccharidosis type I treatment. J Mater Sci Mater Med 28:43.; Osborn et al., 2011Osborn MJ, McElmurry RT, Lees CJ, DeFeo AP, Chen ZY, Kay MA, Naldini L, Freeman G, Tolar J and Blazar BR (2011) Minicircle DNA-based gene therapy coupled with immune modulation permits long-term expression of alpha-L-iduronidase in mice with mucopolysaccharidosis type I. Mol Ther 19:450-460.) |
|
AAV |
IV, temporal vein |
mice, 1 day |
5 months |
Yes |
Yes |
|
(Hartung et al., 2004Hartung SD, Frandsen JL, Pan D, Koniar BL, Graupman P, Gunther R, Low WC, Whitley CB and McIvor RS (2004) Correction of metabolic, craniofacial, and neurologic abnormalities in MPS I mice treated at birth with adeno-associated virus vector transducing the human alpha-L-iduronidase gene. Mol Ther 9:866-875.) |
|
|
IV, cephalic vein |
cats, 3-5 months |
6 months |
Yes |
Yes |
Correction of storage lesions in aorta and myocardium, amelioration of aortic valve disease |
(Hinderer et al., 2014Hinderer C, Bell P, Gurda BL, Wang Q, Louboutin JP, Zhu Y, Bagel J, O’Donnell P, Sikora T, Ruane T et al. (2014) Liver-directed gene therapy corrects cardiovascular lesions in feline mucopolysaccharidosis type I. Proc Natl Acad Sci U S A 111:14894-14899.) |
|
LV |
IV, tail vein |
mice, 8-10 weeks |
1 month |
Yes |
Yes |
Lentiviral vector elicited low immune response, increasing further at later time points |
(Di Domenico et al., 2005Di Domenico C, Villani GR, Di Napoli D, Reyero EG, Lombardo A, Naldini L and Di Natale P (2005) Gene therapy for a mucopolysaccharidosis type I murine model with lentiviral-IDUA vector. Hum Gene Ther 16:81-90.) |
|
|
IV, temporal vein |
mice, 1 day |
20 weeks |
Yes |
Yes |
Newborn mice responded better to treatment |
(Kobayashi et al., 2005Kobayashi H, Carbonaro D, Pepper K, Petersen D, Ge S, Jackson H, Shimada H, Moats R and Kohn DB (2005) Neonatal gene therapy of MPS I mice by intravenous injection of a lentiviral vector. Mol Ther 11:776-789.) |
|
RV |
IV, temporal or tail vein |
mice, 6 weeks |
8 months-old # |
Yes |
Yes |
Reduced GAG in aortic valves and heart, but not in the aorta. Most RV-treated mice had elastic fiber fragmentation and aortic dilatation. Aorta had slight increase in IDUA activity, but not enough to prevent aortic disease. 56% of RV treated mice had aortic insufficiency. |
(Ma et al., 2007Ma X, Liu Y, Tittiger M, Hennig A, Kovacs A, Popelka S, Wang B, Herati R, Bigg M and Ponder KP (2007) Improvements in mucopolysaccharidosis I mice after adult retroviral vector-mediated gene therapy with immunomodulation. Mol Ther 15:889-902.) |
|
|
IV, temporal vein |
mice, 6 weeks |
8 months-old # |
Yes |
Yes |
Aortas remained dilated, with marked GAG storage, and 75% of treated mice had aortic insufficiency. |
(Herati et al., 2008Herati RS, Ma X, Tittiger M, Ohlemiller KK, Kovacs A and Ponder KP (2008) Improved retroviral vector design results in sustained expression after adult gene therapy in mucopolysaccharidosis I mice. J Gene Med 10:972-982.) |
|
|
IV, temporal vein |
mice, 2-3 days |
8 months |
Yes |
Yes |
Prevented aortic dilatation and insuficiency. No significant changes in left ventricular wall thickness, mass index or end-diastolic chamber size. Fractional shortening was significantly greater in high-dose RV mice. |
(Liu et al., 2005Liu Y, Xu L, Hennig AK, Kovacs A, Fu A, Chung S, Lee D, Wang B, Herati RS, Mosinger Ogilvie J, Cai SR and Parker Ponder K (2005) Liver-directed neonatal gene therapy prevents cardiac, bone, ear, and eye disease in mucopolysaccharidosis I mice. Mol Ther 11:35-47.) |
|
|
IV, jugular vein |
dogs, 2-3 days |
up to 21 months |
Yes |
Yes |
Reduction of aortic diameter, reduced mitral valve thickening and reduced elastic fiber fragmentation of aorta. |
(Traas et al., 2007Traas AM, Wang P, Ma X, Tittiger M, Schaller L, O’Donnell P, Sleeper MM, Vite C, Herati R, Aguirre GD et al. (2007) Correction of clinical manifestations of canine mucopolysaccharidosis I with neonatal retroviral vector gene therapy. Mol Ther 15:1423-1431.) |
|
ex vivo RV |
IV, tail vein |
mice, 6-8 weeks |
8 months |
Low |
No |
BMT with RV-modified cells. One mice presented restoration of left ventricular function and normalization of myocites storage vacuoles. |
(Jordan et al., 2005Jordan MC, Zheng Y, Ryazantsev S, Rozengurt N, Roos KP and Neufeld EF (2005) Cardiac manifestations in the mouse model of mucopolysaccharidosis I. Mol Genet Metab 86:233-243.) |
|
ex vivo LV |
|
mice, 2 months |
6 months |
Yes |
Yes |
BMT with LV-modified cells. |
(Visigalli et al., 2010Visigalli I, Delai S, Politi LS, Di Domenico C, Cerri F, Mrak E, D’Isa R, Ungaro D, Stok M, Sanvito F et al. (2010) Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model. Blood 116:5130-5139.) |
MPS II |
plasmid |
electro gene transfer on quadriceps |
mice, 12-16 weeks |
5 weeks |
No |
No |
Transduction was restricted to injection site, had no effect of the heart |
(Friso et al., 2008Friso A, Tomanin R, Zanetti A, Mennuni C, Calvaruso F, La Monica N, Marin O, Zacchello F and Scarpa M (2008) Gene therapy of Hunter syndrome: Evaluation of the efficiency of muscle electro gene transfer for the production and release of recombinant iduronate-2-sulfatase (IDS). Biochim Biophys Acta 1782:574-580.) |
|
AAV |
IV, tail vein |
mice, 2 months |
1 and 7 months |
Yes |
Yes |
(Cardone et al., 2006Cardone M, Polito VA, Pepe S, Mann L, D’Azzo A, Auricchio A, Ballabio A and Cosma MP (2006) Correction of Hunter syndrome in the MPSII mouse model by AAV2/8-mediated gene delivery. Hum Mol Genet 15:1225-1236.) |
|
|
|
IV, tail vein |
mice, 20 weeks |
6 and 24 weeks |
Yes |
Yes |
(Jung et al., 2010Jung SC, Park ES, Choi EN, Kim CH, Kim SJ and Jin DK (2010) Characterization of a novel mucopolysaccharidosis type II mouse model and recombinant AAV2/8 vector-mediated gene therapy. Mol Cells 30:13-18.) |
|
|
AAV9 |
Intrathecal |
Mice, 2 months |
4 months |
Yes |
Yes |
Complete correction of storage lesions in heart, but possibly due to cross-correction from the serum enzyme |
(Motas et al., 2016Motas S, Haurigot V, Garcia M, Marco S, Ribera A, Roca C, Sanchez X, Sanchez V, Molas M, Bertolin J et al. (2016) CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome). JCI Insight 1:e86696.) |
|
|
ICV |
Mice, 2 months |
40 weeks |
Yes |
Yes |
Pilot study compared different routes (intrathecal intravenous and intracerebroventricular). |
(Laoharawee et al., 2017Laoharawee K, Podetz-Pedersen KM, Nguyen TT, Evenstar LB, Kitto KF, Nan Z, Fairbanks CA, Low WC, Kozarsky KF and McIvor RS (2017) Prevention of neurocognitive deficiency in Mucopolysaccharidosis Type II mice by central nervous system-directed, AAV9-mediated iduronate sulfatase gene transfer. Hum Gene Ther 28:626-638.) |
|
|
ICV |
Mice, 2-3 months |
3 weeks |
NA |
Partial |
|
|
|
ex vivo LV |
IV |
mice, 9 weeks |
24 weeks |
Yes |
Yes |
BMT with LV modified cells |
(Wakabayashi et al., 2015Wakabayashi T, Shimada Y, Akiyama K, Higuchi T, Fukuda T, Kobayashi H, Eto Y, Ida H, and Ohashi T (2015) Hematopoietic stem cell gene therapy corrects neuropathic phenotype in murine model of Mucopolysaccharidosis Type II. Hum Gene Ther 26:357-366.) |
MPS IVA |
AAV |
IV |
mice, NS |
12 weeks |
Yes |
NA |
|
(Tomatsu et al., 2012Tomatsu S, Mackenzie WG, Theroux MC, Mason RW, Thacker MM, Shaffer TH, Montano AM, Rowan D, Sly W, Almeciga-Diaz CJ et al. (2012) Current and emerging treatments and surgical interventions for Morquio A syndrome: A review. Res Rep Endocr Disord 2012:65-77.) |
MPS VI |
AAV |
IV and IM |
cats and rats, newborn |
6 months (rat) and 1 year (cat) |
Yes |
Yes |
Vector spread to heart after both IM and IV injections for both animal models |
(Tessitore et al., 2008Tessitore A, Faella A, O’Malley T, Cotugno G, Doria M, Kunieda T, Matarese G, Haskins M and Auricchio A (2008) Biochemical, pathological, and skeletal improvement of mucopolysaccharidosis VI after gene transfer to liver but not to muscle. Mol Ther 16:30-37.) |
|
|
IV, temporal or femoral vein |
rats 5 and 30 days |
6-7 months |
Yes |
Yes |
Pre-treatment with immunosupressionperformed. Heart valve GAG storage was reduced in pre-treated animals. |
(Cotugno et al., 2010Cotugno G, Tessitore A, Capalbo A, Annunziata P, Strisciuglio C, Faella A, Aurilio M, Di Tommaso M, Russo F, Mancini A et al. (2010) Different serum enzyme levels are required to rescue the various systemic features of the mucopolysaccharidoses. Hum Gene Ther 21:555-569.) |
|
|
IV, jugular or cephalic vein |
cats, 5 and 50 days |
12 months |
NA |
NA |
Reduced or normalized mitral valve thickening independent of age of treatment |
(Cotugno et al., 2011Cotugno G, Annunziata P, Tessitore A, O’Malley T, Capalbo A, Faella A, Bartolomeo R, O’Donnell P, Wang P, Russo F et al. (2011) Long-term amelioration of feline Mucopolysaccharidosis VI after AAV-mediated liver gene transfer. Mol Ther 19:461-469.) |
|
|
IV, retro-orbital |
mice, 30 days |
6 or 12 months |
NA |
Yes |
Reduced GAG storage in aortic valves and myocardium |
(Ferla et al., 2014Ferla R, Claudiani P, Cotugno G, Saccone P, De Leonibus E and Auricchio A (2014) Similar therapeutic efficacy between a single administration of gene therapy and multiple administrations of recombinant enzyme in a mouse model of lysosomal storage disease. Hum Gene Ther 25:609-618.) |
|
|
IV, retro-orbital |
Mice, 30 days |
6 months |
Yes |
Yes |
Combined low vector dose with monthly ERT infusions |
(Alliegro et al., 2016Alliegro M, Ferla R, Nusco E, De Leonibus C, Settembre C and Auricchio A (2016) Low-dose gene therapy reduces the frequency of enzyme replacement therapy in a mouse model of lysosomal storage disease. Mol Ther 24:2054-2063.) |
|
|
IV |
Mice, adult |
6 months |
NA |
Yes |
Described safety of the therapy. Minimal GAG reduction in heart valves. |
(Ferla et al., 2017Ferla R, Alliegro M, Marteau JB, Dell’Anno M, Nusco E, Pouillot S, Galimberti S, Valsecchi MG, Zuliani V and Auricchio A (2017) Non-clinical safety and efficacy of an AAV2/8 vector administered intravenously for treatment of Mucopolysaccharidosis Type VI. Mol Ther Methods Clin Dev 6:143-158.) |
|
RV |
IV, jugular vein |
cats, newborn |
6 months to 8 years |
Yes |
Yes |
Supraphysiologic ARSB levels on the bloodstream, but only 9-85% of normal in heart and aorta of treated cats. Treated cats had significant reduced mitral valve thickening, but still developed aortic dilatation, aortic valve regurgitation and thickened aortic valve leaflets. |
(Ponder et al., 2012Ponder KP, O’Malley TM, Wang P, O’Donnell PA, Traas AM, Knox VW, Aguirre GA, Ellinwood NM, Metcalf JA, Wang B et al. (2012) Neonatal gene therapy with a gamma retroviral vector in mucopolysaccharidosis VI cats. Mol Ther 20:898-907.) |
MPS VII |
AAV |
IV, temporal vein |
mice, 2 days |
16 weeks |
Yes |
NA |
|
(Daly et al., 1999Daly TM, Vogler C, Levy B, Haskins ME and Sands MS (1999) Neonatal gene transfer leads to widespread correction of pathology in a murine model of lysosomal storage disease. Proc Natl Acad Sci U S A 96:2296-2300.) |
|
|
Intrahepatic injection |
mice, 7-8 weeks |
24 weeks |
Yes |
Yes |
|
(Sferra et al., 2004Sferra TJ, Backstrom K, Wang C, Rennard R, Miller M and Hu Y (2004) Widespread correction of lysosomal storage following intrahepatic injection of a recombinant adeno-associated virus in the adult MPS VII mouse. Mol Ther 10:478-491.) |
|
LV |
IV, temporal vein |
mice, 2 days |
12 or 18 months |
Yes |
Yes |
Used two MPS VII mouse strains. |
(Derrick-Roberts et al., 2014Derrick-Roberts AL, Pyragius CE, Kaidonis XM, Jackson MR, Anson DS and Byers S (2014) Lentiviral-mediated gene therapy results in sustained expression of beta-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. Hum Gene Ther 25:798-810.) |
|
LV |
IV, tail vein |
Mice, 4 months |
2 months |
Partial |
Partial |
GAG storage in heart only stabilized but not normalized after treatment. |
(Derrick-Roberts et al., 2016Derrick-Roberts AL, Panir K, Pyragius CE, Zarrinkalam KH, Atkins GJ and Byers S (2016) Reversal of established bone pathology in MPS VII mice following lentiviral-mediated gene therapy. Mole Genet Metab 119:249-257.) |
|
RV |
IV, tail vein |
mice, 5-7 weeks |
3 months |
Partial |
No |
Mice were pre-treated with AV-CMV-HGF in the quadriceps. Treatment increased only 5% of GUSB activity in heart |
(Gao et al., 2000Gao C, Sands MS, Haskins ME and Ponder KP (2000) Delivery of a retroviral vector expressing human beta-glucuronidase to the liver and spleen decreases lysosomal storage in mucopolysaccharidosis VII mice. Mol Ther 2:233-244.) |
|
|
IV, jugular vein |
dogs, 2-3 days |
variable, up to 12 months |
Yes |
NA |
Treated dogs had normal valve thickness, no aortic valve insufficiency, mild mitral regurgitation and aortic diameter within normal limits at 8-9 months of age |
(Ponder et al., 2002Ponder KP, Melniczek JR, Xu L, Weil MA, O’Malley TM, O’Donnell PA, Knox VW, Aguirre GD, Mazrier H and Ellinwood NM (2002) Therapeutic neonatal hepatic gene therapy in mucopolysaccharidosis VII dogs. Proc Natl Acad Sci U S A 99:13102-13107.) |
|
|
IV, jugular vein |
dogs, 2-3 days |
24 months |
Yes |
Yes |
Treated dogs had mild mitral regurgitation at 4-5 months of age, which improved over time. At 2 years of age, murmurs were absent and valve thickness was normal. Aortic diameter was within normal limits. Treated dogs had mild improvement in GUSB activity and GAG storage in the aorta. |
(Sleeper et al., 2004Sleeper MM, Fornasari B, Ellinwood NM, Weil MA, Melniczek J, O’Malley TM, Sammarco CD, Xu L, Ponder KP and Haskins ME (2004) Gene therapy ameliorates cardiovascular disease in dogs with mucopolysaccharidosis VII. Circulation 110:815-820.) |
|
|
IV, jugular vein |
dogs, 2-3 days |
variable, up to 8 years |
Yes |
NA |
Aortic dilatation was delayed in RV treated dogs, but it did occur at late times even with stable serum GUSB activity. They presented reduced elastin fragmentation, reduced expression of MMP-12 and of cathepsins B, D, K and S, compared to the untreated group. RV sequences were not found in the aorta. |
(Metcalf et al., 2010Metcalf JA, Linders B, Wu S, Bigg P, O’Donnell P, Sleeper MM, Whyte MP, Haskins M and Ponder KP (2010) Upregulation of elastase activity in aorta in mucopolysaccharidosis I and VII dogs may be due to increased cytokine expression. Mol Genet Metab 99:396-407.) |
|
|
IV, jugular vein |
dogs, 2-3 days |
variable, up to 8 years |
Yes |
Yes |
GAG content in the mitral valve of treated dogs at 8 years post injection was lower than untreated dogs, but still higher than the normal. GUSB activity was 25% of normal in the mitral valves. Treatment reduced total cathepsins activity and increased content of intact collagen. |
(Bigg et al., 2013Bigg PW, Sleeper MM, O’Donnell PA, Liu Y, Wu S, Casal ML, Haskins ME and Ponder KP (2013) The effect of neonatal gene therapy with a gamma retroviral vector on cardiac valve disease in mucopolysaccharidosis VII dogs after a decade. Mol Genet Metab 110:311-318.) |
|
|
IV, temporal vein |
mice, 2-3 days |
6 months |
Yes |
Yes |
Aorta GUSB activity in treated animals was 5-fold de value of normal mice and 325-fold de value of the untreated ones. GAG content reduced to 5% of untreated mice, although stil higher than normal. Reduced aortic dilatation but did not prevent it. |
(Baldo et al., 2011Baldo G, Wu S, Howe RA, Ramamoothy M, Knutsen RH, Fang J, Mecham RP, Liu Y, Wu X, Atkinson JP and Ponder KP (2011) Pathogenesis of aortic dilatation in mucopolysaccharidosis VII mice may involve complement activation. Mol Genet Metab 104:608-619.) |