Different Serum Enzyme Levels Are Required to Rescue the Various Systemic Features of the Mucopolysaccharidoses

Cotugno, Gabriella; Tessitore, Alessandra; Capalbo, Anita; Annunziata, Patrizia; Strisciuglio, Caterina; Faella, Armida; Aurilio, Michela; Tommaso, Maurizio Di; Russo, Fabio; Mancini, Antonio; Leonibus, Elvira De; Aloj, Luigi; Auricchio, Alberto

doi:10.1089/hum.2009.189

Cited by 23 publications

(68 citation statements)

References 70 publications

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“…While the greatest improvements in height and endurance were seen primarily in patients with lower baseline uGAG levels ≤200 µg/mg creatinine, clinical parameters (such as walk distance in 6MWT and pulmonary function) in the high baseline uGAG group remained stable in the ERT group. However, additional or newer approaches may be required to increase the clinical benefit of galsulfase ERT in patients with rapidly progressive disease, such as different dosing schedules [Cotugno et al, 2010]) and/or substrate reduction therapy, both of which have not yet been tested in clinical studies [Schuchman et al, 2013; Simonaro et al, 2010; van Gelder et al, 2012]. Neonatal screening leading to early diagnosis and prompt ERT initiation may be key to improve the management and outcomes of patients with rapidly progressive disease [Furujo et al, 2011; Giugliani 2012; Horovitz et al, 2013; McGill et al, 2010].…”

Section: Discussionmentioning

confidence: 99%

Natural history and galsulfase treatment in mucopolysaccharidosis VI (MPS VI, Maroteaux–Lamy syndrome)—10‐year follow‐up of patients who previously participated in an MPS VI survey study

Giugliani

Lampe

Guffon

et al. 2014

American J of Med Genetics Pt A

123

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Mucopolysaccharidosis VI (MPS VI) is a clinically heterogeneous and progressive disorder with multiorgan manifestations caused by deficient N-acetlylgalactosamine-4-sulfatase activity. A cross-sectional Survey Study in individuals (n=121) affected with MPS VI was conducted between 2001–2002 to establish demographics, urinary glycosaminoglycan (GAG) levels, and clinical progression of disease. We conducted a Resurvey Study (ClinicalTrials.gov: NCT01387854) to obtain 10-year follow-up data, including medical histories and clinical assessments (n=59), and survival status over 12-years (n=117). Patients received a mean (SD) of 6.8 (2.2) years of galsulfase ERT between baseline (Survey Study) and follow-up. ERT patients increased in height by 20.4 cm in the 4–7 year-old baseline age group and by 16.8 cm in the 8–12 year-old baseline age group. ERT patients <13 years old demonstrated improvement in forced vital capacity (FVC) by 68% and forced expiratory volume in 1 second (FEV1) by 55%, and those ≥13 years old increased FVC by 12.8% and maintained FEV1. Patients with >200 µg/mg baseline uGAG levels increased FVC by 48% in the <13 year-old and by 15% in the ≥13 year-old baseline age group. ERT patients who completed the 6-minute walk test demonstrated a mean (SD) increase of 65.7 (100.6) m. Cardiac outcomes did not significantly improve or worsen. Observed mortality rate among naïve patients was 50% (7/14) and 16.5% (17/103) in the ERT group (unadjusted hazard ratio, 0.24; 95% CI, 0.10 to 0.59). Long-term galsulfase ERT was associated with improvements in pulmonary functions and endurance, stabilized cardiac function and increased survival.

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Section: Discussionmentioning

confidence: 99%

Natural history and galsulfase treatment in mucopolysaccharidosis VI (MPS VI, Maroteaux–Lamy syndrome)—10‐year follow‐up of patients who previously participated in an MPS VI survey study

Giugliani

Lampe

Guffon

et al. 2014

American J of Med Genetics Pt A

123

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“…Single systemic administration of AAV2/8 vectors encoding ARSB resulted in long-term production and systemic secretion of therapeutic ARSB from transduced hepatocytes (Cotugno et al, 2012). This resulted in amelioration of the MPS VI phenotype, including reduction of GAG storage and heart valve abnormalities and improvement of long bone length and mobility in both MPS VI rats and cats (Tessitore et al, 2008;Tessitore et al, 2009;Cotugno et al, 2010;Cotugno et al, 2011). These data bode well for clinical translation of AAV2/8-mediated liver gene therapy for MPS VI.…”

Section: Introductionmentioning

confidence: 77%

“…While in MPS VI rats close-to-normal levels of circulating ARSB are required to improve long bone length (Cotugno et al, 2010), in the feline model of MPS VI improvement of long bones can be achieved at lower levels of circulating ARSB obtained with low or intermediate doses of AAV2/8-TBG-fARSB. This could be explained by (1) the different vascularization of long bones or the different levels of mannose 6-phosphate receptor expression between the two species; and (2) the ARSB transgene type, in that we used the species-specific feline transgene in cats, whereas the human transgene was used in MPS VI rats (Cotugno et al 2010).…”

Section: Discussionmentioning

confidence: 99%

“…In our previous studies (Tessitore et al, 2008;Tessitore et al, 2009;Cotugno et al, 2010;Cotugno et al, 2011), performed on rat and cat models of the disease (Yoshida et al, 1993;Yogalingam et al, 1996), we used a gene therapy approach based on intravenous administration of adeno-associated viral vectors based on serotype 8 (AAV2/ 8), which efficiently transduce the liver (Thomas et al, 2004;Gao et al, 2006;Wang et al, 2010b;Nathwani et al, 2011a). Single systemic administration of AAV2/8 vectors encoding ARSB resulted in long-term production and systemic secretion of therapeutic ARSB from transduced hepatocytes (Cotugno et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Gene Therapy for Mucopolysaccharidosis Type VI Is Effective in Cats Without Pre-Existing Immunity to AAV8

et al. 2013

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Liver gene transfer with adeno-associated viral (AAV) 2/8 vectors is being considered for therapy of systemic diseases like mucopolysaccharidosis type VI (MPS VI), a lysosomal storage disease due to deficiency of arylsulfatase B (ARSB). We have previously reported that liver gene transfer with AAV2/8 results in sustained yet variable expression of ARSB. We hypothesized that the variability we observed could be due to pre-existing immunity to wild-type AAV8. To test this, we compared the levels of AAV2/8-mediated transduction in MPS VI cats with and without pre-existing immunity to AAV8. In addition, since levels of lysosomal enzymes as low as 5% of normal are expected to be therapeutic, we evaluated the impact of pre-existing immunity on MPS VI phenotypic rescue. AAV2/8 administration to MPS VI cats without pre-existing neutralizing antibodies to AAV8 resulted in consistent and dose-dependent expression of ARSB, urinary glycosaminoglycan (GAG) reduction, and femur length amelioration. Conversely, animals with pre-existing immunity to AAV8 showed low levels of ARSB expression and limited phenotypic improvement. Our data support the use of AAV2/8-mediated gene transfer for MPS VI and other systemic diseases, and highlight that pre-existing immunity to AAV8 should be considered in determining subject eligibility for therapy.

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“…19,[61][62][63] Hemophilia A and B correction requires a relatively low continuous presence of normal protein in the circulation. Thus, Cantore et al 64 showed that liver-directed lentiviral vectormediated gene therapy of canine hemophilia B dogs provided stable, long-term FIX activity up to 1% of normal with therapeutic benefit.…”

Section: Discussionmentioning

confidence: 99%

Prolonged Expression of Secreted Enzymes in Dogs After Liver-Directed Delivery ofSleeping BeautyTransposons: Implications for Non-Viral Gene Therapy of Systemic Disease

et al. 2017

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The non-viral, integrating Sleeping Beauty (SB) transposon system is efficient in treating systemic monogenic disease in mice, including hemophilia A and B caused by deficiency of blood clotting factors and mucopolysaccharidosis types I and VII caused by a-L-iduronidase (IDUA) and b-glucuronidase (GUSB) deficiency, respectively. Modified approaches of the hydrodynamics-based procedure to deliver transposons to the liver in dogs were recently reported. Using the transgenic canine reporter secreted alkaline phosphatase (cSEAP), transgenic protein in the plasma was demonstrated for up to 6 weeks post infusion. This study reports that immunosuppression of dogs with gadolinium chloride (GdCl 3 ) prolonged the presence of cSEAP in the circulation up to 5.5 months after a single vector infusion. Transgene expression declined gradually but appeared to stabilize after about 2 months at approximately fourfold baseline level. Durability of transgenic protein expression in the plasma was inversely associated with transient increase of liver enzymes alanine transaminase and aspartate transaminase in response to the plasmid delivery procedure, which suggests a deleterious effect of hepatocellular toxicity on transgene expression. GdCl 3 treatment was ineffective for repeat vector infusions. In parallel studies, dogs were infused with potentially therapeutic transposons. Activities of transgenic IDUA and GUSB in plasma peaked at 50-350% of wildtype, but in the absence of immunosuppression lasted only a few days. Transposition was detectable by excision assay only when the most efficient transposase, SB100X, was used. Dogs infused with transposons encoding canine clotting factor IX (cFIX) were treated with GdCl 3 and showed expression profiles similar to those in cSEAP-infused dogs, with expression peaking at 40% wt (2 lg/mL). It is concluded that GdCl 3 can support extended transgene expression after hydrodynamic introduction of SB transposons in dogs, but that alternative regimens will be required to achieve therapeutic levels of transgene products.

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Different Serum Enzyme Levels Are Required to Rescue the Various Systemic Features of the Mucopolysaccharidoses

Cited by 23 publications

References 70 publications

Natural history and galsulfase treatment in mucopolysaccharidosis VI (MPS VI, Maroteaux–Lamy syndrome)—10‐year follow‐up of patients who previously participated in an MPS VI survey study

Natural history and galsulfase treatment in mucopolysaccharidosis VI (MPS VI, Maroteaux–Lamy syndrome)—10‐year follow‐up of patients who previously participated in an MPS VI survey study

Gene Therapy for Mucopolysaccharidosis Type VI Is Effective in Cats Without Pre-Existing Immunity to AAV8

Prolonged Expression of Secreted Enzymes in Dogs After Liver-Directed Delivery ofSleeping BeautyTransposons: Implications for Non-Viral Gene Therapy of Systemic Disease

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