Charles A. O'Neill, PhD

Dr. O'Neill is Assistant Adjunct Professor in the Pharmacology and Toxicology Graduate Group at University of California-Davis. He has contributed to 26 regulatory submissions in the US, EU, Australia and Japan, coauthored over 40 peer-reviewed publications, and been a Diplomate of the American Board of Toxicology since 1995. With 14 years of biotechnology and pharmaceutical development experience, Dr. O'Neill has led non-clinical development efforts regarding anti-angiogenic molecules including the targeted oncology monoclonal antibody AvastinTM, and the intra-vitreally delivered monoclonal antibody fragment LucentisTM, a treatment for the neovascular form of age-related macular degeneration.

Discipline: Regulatory Affairs

Recent Publications

2017

Maternal Phenylketonuria syndrome: Studies in mice suggest a potential approach to a continuing problem.

Pediatr Res. 2017 Dec 21;:

Authors: Zeile WL, McCune HC, Musson DG, O'Donnell B, O'Neill CA, Tsuruda LS, Zori RT, Laipis PJ

Maternal Phenylketonuria syndrome: Studies in mice suggest a potential approach to a continuing problem.

Pediatr Res. 2017 Dec 21;:

Authors: Zeile WL, McCune HC, Musson DG, O'Donnell B, O'Neill CA, Tsuruda LS, Zori RT, Laipis PJ

Abstract
BACKGROUND: Untreated Phenylketonuria (PKU), one of the most common human genetic disorders, usually results in mental retardation. While a protein-restricted artificial diet can prevent retardation, dietary compliance in adults is often poor. In pregnant PKU women, noncompliance can result in maternal PKU syndrome, where high phenylalanine (Phe) levels cause severe fetal complications. Enzyme substitution therapy using phenylalanine ammonia lyase (PAL) corrects PKU in BTBR phenylalanine hydroxylase (Pahenu2) mutant mice, suggesting a potential for maternal PKU syndrome treatment in humans.
METHODS: We reviewed clinical data to assess maternal PKU syndrome incidence in pregnant PKU women. We treated female PKU mice (on normal diet) with PAL, stabilizing Phe at physiological levels, and mated them to assess pregnancy outcomesRESULTS:Patient records show that, unfortunately, the efficacy of diet to prevent maternal PKU syndrome has not significantly improved since the problem was first noted forty years ago. PAL treatment of pregnant PKU mice show that offspring of PAL-treated dams survive to adulthood, in contrast to the complete lethality seen in untreated mice or limited survival see in mice on a PKU diet.
CONCLUSION: PAL treatment reduced maternal PKU syndrome severity in mice and may have potential for human PKU therapy.Pediatric Research accepted article preview online, 21 December 2017. doi:10.1038/pr.2017.323.

PMID: 29278642 [PubMed - as supplied by publisher]

Maternal Phenylketonuria syndrome: Studies in mice suggest a potential approach to a continuing problem.

Pediatr Res. 2017 Dec 21;:

Authors: Zeile WL, McCune HC, Musson DG, O'Donnell B, O'Neill CA, Tsuruda LS, Zori RT, Laipis PJ

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Gene Therapy with BMN 270 Results in Therapeutic Levels of FVIII in Mice and Primates and Normalization of Bleeding in Hemophilic Mice.

Mol Ther. 2017 Dec 14;:

Authors: Bunting S, Zhang L, Xie L, Bullens S, Mahimkar R, Fong S, Sandza K, Harmon D, Yates B, Handyside B, Sihn CR, Galicia N, Tsuruda L, O'Neill CA, Bagri A, Colosi P, Long S, Vehar G, Carter B

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Gene Therapy with BMN 270 Results in Therapeutic Levels of FVIII in Mice and Primates and Normalization of Bleeding in Hemophilic Mice.

Mol Ther. 2017 Dec 14;:

Authors: Bunting S, Zhang L, Xie L, Bullens S, Mahimkar R, Fong S, Sandza K, Harmon D, Yates B, Handyside B, Sihn CR, Galicia N, Tsuruda L, O'Neill CA, Bagri A, Colosi P, Long S, Vehar G, Carter B

Abstract
Hemophilia A is an X-linked bleeding disorder caused by mutations in the gene encoding the factor VIII (FVIII) coagulation protein. Bleeding episodes in patients are reduced by prophylactic therapy or treated acutely using recombinant or plasma-derived FVIII. We have made an adeno-associated virus 5 vector containing a B domain-deleted (BDD) FVIII gene (BMN 270) with a liver-specific promoter. BMN 270 injected into hemophilic mice resulted in a dose-dependent expression of BDD FVIII protein and a corresponding correction of bleeding time and blood loss. At the highest dose tested, complete correction was achieved. Similar corrections in bleeding were observed at approximately the same plasma levels of FVIII protein produced either endogenously by BMN 270 or following exogenous administration of recombinant BDD FVIII. No evidence of liver dysfunction or hepatocyte endoplasmic reticulum stress was observed. Comparable doses in primates produced similar levels of circulating FVIII. These preclinical data support evaluation of BMN 270 in hemophilia A patients.

PMID: 29292164 [PubMed - as supplied by publisher]

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Gene Therapy with BMN 270 Results in Therapeutic Levels of FVIII in Mice and Primates and Normalization of Bleeding in Hemophilic Mice.

Mol Ther. 2017 Dec 14;:

Authors: Bunting S, Zhang L, Xie L, Bullens S, Mahimkar R, Fong S, Sandza K, Harmon D, Yates B, Handyside B, Sihn CR, Galicia N, Tsuruda L, O'Neill CA, Bagri A, Colosi P, Long S, Vehar G, Carter B

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Partial rescue of neuropathology in the murine model of PKU following administration of recombinant phenylalanine ammonia lyase (pegvaliase).

Mol Genet Metab. 2017 Apr 29;:

Authors: Goldfinger M, Zeile WL, Corado CR, O'Neill CA, Tsuruda LS, Laipis PJ, Cooper JD

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Partial rescue of neuropathology in the murine model of PKU following administration of recombinant phenylalanine ammonia lyase (pegvaliase).

Mol Genet Metab. 2017 Apr 29;:

Authors: Goldfinger M, Zeile WL, Corado CR, O'Neill CA, Tsuruda LS, Laipis PJ, Cooper JD

Abstract
Pegylated recombinant phenylalanine ammonia lyase (pegvaliase) is an enzyme substitution therapy being evaluated for the treatment of phenylketonuria (PKU). PKU is characterized by elevated plasma phenylalanine, which is thought to lead to a deficiency in monoamine neurotransmitters and ultimately, neurocognitive dysfunction. A natural history evaluation in a mouse model of PKU demonstrated a profound decrease in tyrosine hydroxylase (TH) immunoreactivity in several brain regions, beginning at 4weeks of age. Following treatment with pegvaliase, the number of TH positive neurons was increased in several brain regions compared to placebo treated ENU2 mice.

PMID: 28506393 [PubMed - as supplied by publisher]

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Partial rescue of neuropathology in the murine model of PKU following administration of recombinant phenylalanine ammonia lyase (pegvaliase).

Mol Genet Metab. 2017 Apr 29;:

Authors: Goldfinger M, Zeile WL, Corado CR, O'Neill CA, Tsuruda LS, Laipis PJ, Cooper JD

2016

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Reveglucosidase alfa (BMN 701), an IGF 2 Tagged rhAcid α-Glucosidase, Improves Respiratory Functional Parameters in a Murine Model of Pompe Disease.

J Pharmacol Exp Ther. 2016 Nov 16;:

Authors: Peng J, Dalton J, Butt M, Tracy K, Kennedy D, Haroldsen P, Cahayag R, Zoog S, O'Neill CA, Tsuruda L

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Reveglucosidase alfa (BMN 701), an IGF 2 Tagged rhAcid α-Glucosidase, Improves Respiratory Functional Parameters in a Murine Model of Pompe Disease.

J Pharmacol Exp Ther. 2016 Nov 16;:

Authors: Peng J, Dalton J, Butt M, Tracy K, Kennedy D, Haroldsen P, Cahayag R, Zoog S, O'Neill CA, Tsuruda L

Abstract
Pompe disease is a rare neuromuscular disorder caused by an acid α-glucosidase (GAA) deficiency resulting in glycogen accumulation in muscle, leading to myopathy and respiratory weakness. Reveglucosidase alfa (BMN 701), is an insulin-like growth factor 2 (IGF2) tagged rhGAA that enhances rhGAA cellular uptake via a glycosylation independent IGF2-binding region of the cation-independent mannose-6-phosphate receptor (CI-MPR). These studies evaluated the effects of reveglucosidase alfa treatment on glycogen clearance in muscle relative to rhGAA as well as changes in respiratory function and glycogen clearance in respiratory related tissue in a Pompe mouse model (GAA(tm1Rabn)). In a comparison of glycogen clearance in muscle with reveglucosidase alfa and rhGAA, reveglucosidase alfa was more effective than rhGAA with 2.8 to 4.7 lower EC50 values, likely due to increased cellular uptake. The effect of weekly intravenous (IV) administration of reveglucosidase alfa on respiratory function was monitored in Pompe and wild type mice using whole body plethysmography under normoxic and hypercapnic conditions. Over 12-weeks of 20 mg/kg reveglucosidase alfa treatment in Pompe mice, peak inspiratory flow (PIF) and peak expiratory flow (PEF) stabilized with no compensation in respiratory rate and inspiratory time during hypercapnic and recovery conditions compared to vehicle-treated Pompe mice. Dose related decreases in glycogen levels in both ambulatory and respiratory muscles generally correlated to changes in respiratory function. Improvement of murine PIF and PEF were similar in magnitude to increases in maximal inspiratory and expiratory pressure observed clinically in late onset Pompe patients treated with reveglucosidase alfa (Byrne et al, in preparation).

PMID: 27856936 [PubMed - as supplied by publisher]

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Reveglucosidase alfa (BMN 701), an IGF 2 Tagged rhAcid α-Glucosidase, Improves Respiratory Functional Parameters in a Murine Model of Pompe Disease.

J Pharmacol Exp Ther. 2016 Nov 16;:

Authors: Peng J, Dalton J, Butt M, Tracy K, Kennedy D, Haroldsen P, Cahayag R, Zoog S, O'Neill CA, Tsuruda L

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Antibodies that neutralize cellular uptake of elosulfase alfa are not associated with reduced efficacy or pharmacodynamic effect in individuals with Morquio A syndrome.

J Immunol Methods. 2016 Oct 24;:

Authors: Melton AC, Soon RK, Tompkins T, Long B, Schweighardt B, Qi Y, Vitelli C, Bagri A, Decker C, O'Neill CA, Zoog SJ, Jesaitis L

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Antibodies that neutralize cellular uptake of elosulfase alfa are not associated with reduced efficacy or pharmacodynamic effect in individuals with Morquio A syndrome.

J Immunol Methods. 2016 Oct 24;:

Authors: Melton AC, Soon RK, Tompkins T, Long B, Schweighardt B, Qi Y, Vitelli C, Bagri A, Decker C, O'Neill CA, Zoog SJ, Jesaitis L

Abstract
Many enzyme replacement therapies (ERTs) for lysosomal storage disorders use the cell-surface cation-independent mannose-6 phosphate receptor (CI-M6PR) to deliver ERTs to the lysosome. However, neutralizing antibodies (NAb) may interfere with this process. We previously reported that most individuals with Morquio A who received elosulfase alfa in the phase 3 MOR-004 trial tested positive for NAbs capable of interfering with binding to CI-M6PR ectodomain in an ELISA-based assay. However, no correlation was detected between NAb occurrence and clinical efficacy or pharmacodynamics. To quantify and better characterize the impact of NAbs, we developed a functional cell-based flow cytometry assay with a titer step that detects antibodies capable of interfering with elosulfase alfa uptake. Serum samples collected during the MOR-004 trial were tested and titers were determined. Consistent with earlier findings on NAb positivity, no correlations were observed between NAb titers and the clinical outcomes of elosulfase alfa-treated individuals with Morquio A.

PMID: 27789297 [PubMed - as supplied by publisher]

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Antibodies that neutralize cellular uptake of elosulfase alfa are not associated with reduced efficacy or pharmacodynamic effect in individuals with Morquio A syndrome.

J Immunol Methods. 2016 Oct 24;:

Authors: Melton AC, Soon RK, Tompkins T, Long B, Schweighardt B, Qi Y, Vitelli C, Bagri A, Decker C, O'Neill CA, Zoog SJ, Jesaitis L

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Workshop Proceedings: Streamlined Development of Safety Assessment Programs Supporting Orphan/Rare Diseases-Are We There Yet?

Int J Toxicol. 2016 Jul;35(4):393-409

Authors: Allamneni KP, Parker S, O'Neill CA, Wright TL, King S, Andrews L

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Workshop Proceedings: Streamlined Development of Safety Assessment Programs Supporting Orphan/Rare Diseases-Are We There Yet?

Int J Toxicol. 2016 Jul;35(4):393-409

Authors: Allamneni KP, Parker S, O'Neill CA, Wright TL, King S, Andrews L

Abstract
A workshop entitled "Streamlined Development of Safety Assessment Programs Supporting Orphan/Rare Diseases-Are We There Yet?" was held at the 36th Annual Meeting of the American College of Toxicology in Summerlin, Nevada. The workshop was sponsored by Shire and Ultragenyx and was designed to present the nonclinical considerations for the development of various products for rare diseases. A panel of experts from industry and government highlighted the nonclinical considerations in developing toxicology programs supporting rare disease therapeutics, challenges in preclinical safety assessment, reviewed the current guidance, and presented the progress that has been made to date. The main learning from the workshop was that nonclinical testing of therapeutics targeting rare disease warrants special considerations, and early collaboration between sponsors and health authorities may help optimize the scope and timing of the supportive studies. Specific examples for nonclinical development programs for enzyme replacement therapy (ERT) were presented. Although the symposium focused on ERTs, the concepts are broadly applicable.

PMID: 27272885 [PubMed - in process]

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Workshop Proceedings: Streamlined Development of Safety Assessment Programs Supporting Orphan/Rare Diseases-Are We There Yet?

Int J Toxicol. 2016 Jul;35(4):393-409

Authors: Allamneni KP, Parker S, O'Neill CA, Wright TL, King S, Andrews L

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Pharmacodynamics, pharmacokinetics and biodistribution of recombinant human N-acetylgalactosamine 4-sulfatase after 6months of therapy in cats using different IV infusion durations.

Mol Genet Metab. 2016 Feb;117(2):157-63

Authors: Ruane T, Haskins M, Cheng A, Wang P, Aguirre G, Knox VW, Qi Y, Tompkins T, O'Neill CA

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Pharmacodynamics, pharmacokinetics and biodistribution of recombinant human N-acetylgalactosamine 4-sulfatase after 6months of therapy in cats using different IV infusion durations.

Mol Genet Metab. 2016 Feb;117(2):157-63

Authors: Ruane T, Haskins M, Cheng A, Wang P, Aguirre G, Knox VW, Qi Y, Tompkins T, O'Neill CA

Abstract
BACKGROUND: Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease characterized by an absence or marked reduction of lysosomal N-acetylgalactosamine-4-sulfatase activity. Affected individuals have widespread accumulation of unmetabolized glycosaminoglycan substrates leading to detrimental effects. Recombinant human N-acetylgalactosamine 4-sulfatase (rhASB) is an approved enzyme replacement therapy for patients with MPS VI. Despite the known efficacy of weekly 4-h rhASB infusions, some clinicians wish to treat patients using reduced infusion times. This study compared the pharmacodynamics, pharmacokinetics, and tissue biodistribution of rhASB when administered as 2- and 4-h intravenous infusions using a feline model of MPS VI.
METHODS: Study animals were MPS VI-affected cats that demonstrate clinical signs and biochemical derangements similar to human MPS VI patients. Beginning at age 4weeks, animals received weekly 2-h (N=6) or 4-h (N=6) IV infusions of rhASB for 26weeks (Naglazyme® [galsulfase] Solution for Intravenous Infusion; BioMarin Pharmaceutical, Inc.). The control group consisted of untreated MPS VI-affected cats (N=6). The pharmacokinetic parameters of plasma rhASB and urinary glycosaminoglycan were determined at weeks 13 and 26. Animals were euthanized 48h after the last infusion and tissue concentration of ASB, GAG and β-glucuronidase were measured in the liver, spleen, aorta, and kidney. Skeletal and ophthalmological evaluations were performed within 2weeks of euthanasia.
RESULTS: At week 13, the mean AUC0-t in animals treated with 4-h infusions was similar to 2-h infusions while the Cmax of the 4-h infusion was 50% of the 2-h infusion. By week 26, the mean AUC0-t of the 4-h infusion was 1.3-fold higher than the 2-h infusion (p<0.05) while Cmax of the 4-h infusion was 70% of the 2-h infusion (p<0.05). Among animals treated with 2- and 4-h infusions, there was no difference in urinary GAG excretion, tissue GAG storage, tissue galsulfase activity, and β-glucuronidase but all were significantly different than control animals (for each, p<0.001). Radiographic skeletal abnormality scores for animals were also similar for both treatment groups and significantly higher than control animals (p<0.001). There was no significant difference in corneal clouding scores among treated and untreated animals.
CONCLUSIONS: There was no significant difference in clinical outcomes when rhASB was administered to MPS VI affected cats as 2- and 4-h infusions over 26weeks. Additional studies may determine if shorter infusion times are appropriate for MPS VI patients without significant infusion-associated reactions.

PMID: 26776148 [PubMed - in process]

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Pharmacodynamics, pharmacokinetics and biodistribution of recombinant human N-acetylgalactosamine 4-sulfatase after 6months of therapy in cats using different IV infusion durations.

Mol Genet Metab. 2016 Feb;117(2):157-63

Authors: Ruane T, Haskins M, Cheng A, Wang P, Aguirre G, Knox VW, Qi Y, Tompkins T, O'Neill CA

2015

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Immunogenicity of Elosulfase Alfa, an Enzyme Replacement Therapy in Patients With Morquio A Syndrome: Results From MOR-004, a Phase III Trial.

Clin Ther. 2015 May 1;37(5):1012-1021.e6

Authors: Schweighardt B, Tompkins T, Lau K, Jesaitis L, Qi Y, Musson DG, Farmer P, Haller C, Shaywitz AJ, Yang K, O'Neill CA

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Immunogenicity of Elosulfase Alfa, an Enzyme Replacement Therapy in Patients With Morquio A Syndrome: Results From MOR-004, a Phase III Trial.

Clin Ther. 2015 May 1;37(5):1012-1021.e6

Authors: Schweighardt B, Tompkins T, Lau K, Jesaitis L, Qi Y, Musson DG, Farmer P, Haller C, Shaywitz AJ, Yang K, O'Neill CA

Abstract
PURPOSE: Morquio A syndrome (mucopolysaccharidosis IVA [MPS IVA]) is a lysosomal storage disorder caused by deficiency of the enzyme N-acetylgalactosamine-6-sulfatase, which is required to degrade the glycosaminoglycan keratan sulfate. Morquio A is associated with extensive morbidity and early mortality. Elosulfase alfa is an enzyme replacement therapy that provides a treatment option for patients with Morquio A. We examined the immunogenicity profile of elosulfase alfa, assessing any correlations between antidrug antibodies and the efficacy and safety outcomes in 176 patients with Morquio A from a 24-week international Phase III trial.
METHODS: Patients were randomized to placebo (n = 59) or elosulfase alfa 2.0 mg/kg administered weekly (n = 58) or every other week (n = 59) as an ~4-hour infusion. Blood samples were routinely tested to determine drug-specific total antibody titer and neutralizing antibody (NAb) positivity. Drug-specific immunoglobulin E positivity was tested routinely and in response to severe hypersensitivity adverse events (AEs). Antidrug antibody positivity and titer were compared with efficacy and safety metrics to assess possible correlations.
FINDINGS: The 176 patients in the trial were 54% female, with a mean age of 11.9 years. In all patients treated with elosulfase alfa antidrug antibodies developed, and in the majority, antibodies capable of interfering with cation-independent mannose-6-phosphate receptor binding in vitro (NAb) developed. Less than 10% of patients tested positive for drug-specific IgE during the study. Despite the high incidence of anti-elosulfase alfa antibodies, no correlations were detected between higher total antibody titers or NAb positivity and worsened 6-minute walk test results, urine keratin sulfate levels, or hypersensitivity AEs. Drug-specific IgE positivity had no apparent association with the occurrence of anaphylaxis, other hypersensitivity AEs, and/or treatment withdrawal.
IMPLICATIONS: Despite the universal development of antidrug antibodies, elosulfase alfa treatment was both safe and well tolerated and immunogenicity was not associated with reduced treatment effect. ClinicalTrials.gov identifier: NCT01275066. (Clin Ther.

PMID: 25487082 [PubMed - in process]

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Immunogenicity of Elosulfase Alfa, an Enzyme Replacement Therapy in Patients With Morquio A Syndrome: Results From MOR-004, a Phase III Trial.

Clin Ther. 2015 May 1;37(5):1012-1021.e6

Authors: Schweighardt B, Tompkins T, Lau K, Jesaitis L, Qi Y, Musson DG, Farmer P, Haller C, Shaywitz AJ, Yang K, O'Neill CA

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Genetic variation in aryl N-acetyltransferase results in significant differences in the pharmacokinetic and safety profiles of amifampridine (3,4-diaminopyridine) phosphate.

Pharmacol Res Perspect. 2015 Feb;3(1):e00099

Authors: Haroldsen PE, Garovoy MR, Musson DG, Zhou H, Tsuruda L, Hanson B, O'Neill CA

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Genetic variation in aryl N-acetyltransferase results in significant differences in the pharmacokinetic and safety profiles of amifampridine (3,4-diaminopyridine) phosphate.

Pharmacol Res Perspect. 2015 Feb;3(1):e00099

Authors: Haroldsen PE, Garovoy MR, Musson DG, Zhou H, Tsuruda L, Hanson B, O'Neill CA

Abstract
The clinical use of amifampridine phosphate for neuromuscular junction disorders is increasing. The metabolism of amifampridine occurs via polymorphic aryl N-acetyltransferase (NAT), yet its pharmacokinetic (PK) and safety profiles, as influenced by this enzyme system, have not been investigated. The objective of this study was to assess the effect of NAT phenotype and genotype on the PK and safety profiles of amifampridine in healthy volunteers (N = 26). A caffeine challenge test and NAT2 genotyping were used to delineate subjects into slow and fast acetylators for PK and tolerability assessment of single, escalating doses of amifampridine (up to 30 mg) and in multiple daily doses (20 mg QID) of amifampridine. The results showed that fast acetylator phenotypes displayed significantly lower C max, AUC, and shorter t 1/2 for amifampridine than slow acetylators. Plasma concentrations of the N-acetyl metabolite were approximately twofold higher in fast acetylators. Gender differences were not observed. Single doses of amifampridine demonstrated dose linear PKs. Amifampridine achieved steady state plasma levels within 1 day of dosing four times daily. No accumulation or time-dependent changes in amifampridine PK parameters occurred. Overall, slow acetylators reported 73 drug-related treatment-emergent adverse events versus 6 in fast acetylators. Variations in polymorphic NAT corresponding with fast and slow acetylator phenotypes significantly affects the PK and safety profiles of amifampridine.

PMID: 25692017 [PubMed]

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Genetic variation in aryl N-acetyltransferase results in significant differences in the pharmacokinetic and safety profiles of amifampridine (3,4-diaminopyridine) phosphate.

Pharmacol Res Perspect. 2015 Feb;3(1):e00099

Authors: Haroldsen PE, Garovoy MR, Musson DG, Zhou H, Tsuruda L, Hanson B, O'Neill CA

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Nonclinical evaluation of CNS-administered TPP1 enzyme replacement in canine CLN2 neuronal ceroid lipofuscinosis.

Mol Genet Metab. 2015 Feb;114(2):281-93

Authors: Vuillemenot BR, Kennedy D, Cooper JD, Wong AM, Sri S, Doeleman T, Katz ML, Coates JR, Johnson GC, Reed RP, Adams EL, Butt MT, Musson DG, Henshaw J, Keve S, Cahayag R, Tsuruda LS, O'Neill CA

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Nonclinical evaluation of CNS-administered TPP1 enzyme replacement in canine CLN2 neuronal ceroid lipofuscinosis.

Mol Genet Metab. 2015 Feb;114(2):281-93

Authors: Vuillemenot BR, Kennedy D, Cooper JD, Wong AM, Sri S, Doeleman T, Katz ML, Coates JR, Johnson GC, Reed RP, Adams EL, Butt MT, Musson DG, Henshaw J, Keve S, Cahayag R, Tsuruda LS, O'Neill CA

Abstract
The CLN2 form of neuronal ceroid lipofuscinosis, a type of Batten disease, is a lysosomal storage disorder caused by a deficiency of the enzyme tripeptidyl peptidase-1 (TPP1). Patients exhibit progressive neurodegeneration and loss of motor, cognitive, and visual functions, leading to death by the early teenage years. TPP1-null Dachshunds recapitulate human CLN2 disease. To characterize the safety and pharmacology of recombinant human (rh) TPP1 administration to the cerebrospinal fluid (CSF) as a potential enzyme replacement therapy (ERT) for CLN2 disease, TPP1-null and wild-type (WT) Dachshunds were given repeated intracerebroventricular (ICV) infusions and the pharmacokinetic (PK) profile, central nervous system (CNS) distribution, and safety were evaluated. TPP1-null animals and WT controls received 4 or 16mg of rhTPP1 or artificial cerebrospinal fluid (aCSF) vehicle every other week. Elevated CSF TPP1 concentrations were observed for 2-3 days after the first ICV infusion and were approximately 1000-fold higher than plasma levels at the same time points. Anti-rhTPP1 antibodies were detected in CSF and plasma after repeat rhTPP1 administration, with titers generally higher in TPP1-null than in WT animals. Widespread brain distribution of rhTPP1 was observed after chronic administration. Expected histological changes were present due to the CNS delivery catheters and were similar in rhTPP1 and vehicle-treated animals, regardless of genotype. Neuropathological evaluation demonstrated the clearance of lysosomal storage, preservation of neuronal morphology, and reduction in brain inflammation with treatment. This study demonstrates the favorable safety and pharmacology profile of rhTPP1 ERT administered directly to the CNS and supports clinical evaluation in patients with CLN2 disease.

PMID: 25257657 [PubMed - in process]

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Nonclinical evaluation of CNS-administered TPP1 enzyme replacement in canine CLN2 neuronal ceroid lipofuscinosis.

Mol Genet Metab. 2015 Feb;114(2):281-93

Authors: Vuillemenot BR, Kennedy D, Cooper JD, Wong AM, Sri S, Doeleman T, Katz ML, Coates JR, Johnson GC, Reed RP, Adams EL, Butt MT, Musson DG, Henshaw J, Keve S, Cahayag R, Tsuruda LS, O'Neill CA

2014

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Pharmacokinetic and pharmacodynamic evaluation of elosulfase alfa, an enzyme replacement therapy in patients with Morquio A syndrome.

Clin Pharmacokinet. 2014 Dec;53(12):1137-47

Authors: Qi Y, Musson DG, Schweighardt B, Tompkins T, Jesaitis L, Shaywitz AJ, Yang K, O'Neill CA

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Pharmacokinetic and pharmacodynamic evaluation of elosulfase alfa, an enzyme replacement therapy in patients with Morquio A syndrome.

Clin Pharmacokinet. 2014 Dec;53(12):1137-47

Authors: Qi Y, Musson DG, Schweighardt B, Tompkins T, Jesaitis L, Shaywitz AJ, Yang K, O'Neill CA

Abstract
BACKGROUND AND OBJECTIVES: Morquio A syndrome (mucopolysaccharidosis IVA; MPS IVA) is a lysosomal storage disorder caused by deficiency of N-acetylgalactosamine-6-sulfatase, an enzyme required for degradation of the glycosaminoglycan keratan sulfate. Enzyme replacement therapy with elosulfase alfa provides a potential therapy for Morquio A syndrome. We analyzed the pharmacokinetics and pharmacodynamics of elosulfase alfa in Morquio A patients from a phase III clinical trial.
METHODS: In a randomized double-blind study, elosulfase alfa at 2.0 mg/kg was administrated weekly or every other week for 24 weeks. Pharmacokinetic parameters of elosulfase alfa were determined at weeks 0 and 22 by non-compartmental analysis. Safety was assessed throughout the study. The relationship of pharmacokinetic parameters to patient demographics, pharmacodynamic assessments, immunogenicity, and efficacy and safety outcomes were assessed graphically by treatment group.
RESULTS: Elosulfase alfa exposure and half-life (t(½)) increased for both dose regimens during the study. There appeared to be no consistent trend between drug clearance (CL) and patient's sex, race, body weight, or age. All patients developed anti-drug antibodies, but no association was noted between total antibody titer and CL. In contrast, positive neutralizing antibody (NAb) status appeared to associate with decreased CL and prolonged t(½) for patients in the cohort dosed weekly. NAb may interfere with receptor-mediated cellular uptake and lead to increased circulation time of elosulfase alfa.
CONCLUSION: Despite the association between NAb and decreased drug clearance, neither dosing cohort showed associations between drug exposure and change in urinary keratan sulfate, 6-min walk test distances, or the occurrence of adverse events.

PMID: 25234648 [PubMed - in process]

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Pharmacokinetic and pharmacodynamic evaluation of elosulfase alfa, an enzyme replacement therapy in patients with Morquio A syndrome.

Clin Pharmacokinet. 2014 Dec;53(12):1137-47

Authors: Qi Y, Musson DG, Schweighardt B, Tompkins T, Jesaitis L, Shaywitz AJ, Yang K, O'Neill CA

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Enzyme replacement therapy attenuates disease progression in a canine model of late-infantile neuronal ceroid lipofuscinosis (CLN2 disease).

J Neurosci Res. 2014 Nov;92(11):1591-8

Authors: Katz ML, Coates JR, Sibigtroth CM, Taylor JD, Carpentier M, Young WM, Wininger FA, Kennedy D, Vuillemenot BR, O'Neill CA

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Enzyme replacement therapy attenuates disease progression in a canine model of late-infantile neuronal ceroid lipofuscinosis (CLN2 disease).

J Neurosci Res. 2014 Nov;92(11):1591-8

Authors: Katz ML, Coates JR, Sibigtroth CM, Taylor JD, Carpentier M, Young WM, Wininger FA, Kennedy D, Vuillemenot BR, O'Neill CA

Abstract
Using a canine model of classical late-infantile neuronal ceroid lipofuscinosis (CLN2 disease), a study was conducted to evaluate the potential pharmacological activity of recombinant human tripeptidyl peptidase-1 (rhTPP1) enzyme replacement therapy administered directly to the cerebrospinal fluid (CSF). CLN2 disease is a hereditary neurodegenerative disorder resulting from mutations in CLN2, which encodes the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Infants with mutations in both CLN2 alleles develop normally but in the late-infantile/early-childhood period undergo progressive neurological decline accompanied by pronounced brain atrophy. The disorder, a form of Batten disease, is uniformly fatal, with clinical signs starting between 2 and 4 years of age and death usually occurring by the early teenage years. Dachshunds homozygous for a null mutation in the canine ortholog of CLN2 (TPP1) exhibit a similar disorder that progresses to end stage at 10.5-11 months of age. Administration of rhTPP1 via infusion into the CSF every other week, starting at approximately 2.5 months of age, resulted in dose-dependent significant delays in disease progression, as measured by delayed onset of neurologic deficits, improved performance on a cognitive function test, reduced brain atrophy, and increased life span. Based on these findings, a clinical study evaluating the potential therapeutic value of rhTPP1 administration into the CSF of children with CLN2 disease has been initiated.

PMID: 24938720 [PubMed - indexed for MEDLINE]

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Enzyme replacement therapy attenuates disease progression in a canine model of late-infantile neuronal ceroid lipofuscinosis (CLN2 disease).

J Neurosci Res. 2014 Nov;92(11):1591-8

Authors: Katz ML, Coates JR, Sibigtroth CM, Taylor JD, Carpentier M, Young WM, Wininger FA, Kennedy D, Vuillemenot BR, O'Neill CA

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Enzyme replacement therapy delays pupillary light reflex deficits in a canine model of late infantile neuronal ceroid lipofuscinosis.

Exp Eye Res. 2014 Aug;125:164-72

Authors: Whiting RE, Narfström K, Yao G, Pearce JW, Coates JR, Castaner LJ, Jensen CA, Dougherty BN, Vuillemenot BR, Kennedy D, O'Neill CA, Katz ML

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Enzyme replacement therapy delays pupillary light reflex deficits in a canine model of late infantile neuronal ceroid lipofuscinosis.

Exp Eye Res. 2014 Aug;125:164-72

Authors: Whiting RE, Narfström K, Yao G, Pearce JW, Coates JR, Castaner LJ, Jensen CA, Dougherty BN, Vuillemenot BR, Kennedy D, O'Neill CA, Katz ML

Abstract
Late-infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a hereditary neurological disorder characterized by progressive retinal degeneration and vision loss, cognitive and motor decline, seizures, and pronounced brain atrophy. This fatal pediatric disease is caused by mutations in the CLN2 gene which encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Utilizing a TPP1-/- Dachshund model of CLN2 disease, studies were conducted to assess the effects of TPP1 enzyme replacement administered directly to the CNS on disease progression. Recombinant human TPP1 (rhTPP1) or artificial cerebrospinal fluid vehicle was administered to CLN2-affected dogs via infusion into the CSF. Untreated and vehicle treated affected dogs exhibited progressive declines in pupillary light reflexes (PLRs) and electroretinographic (ERG) responses to light stimuli. Studies were undertaken to determine whether CSF administration of rhTPP1 alters progression of the PLR and ERG deficits in the canine model. rhTPP1 administration did not inhibit the decline in ERG responses, as rhTPP1 treated, vehicle treated, and untreated dogs all exhibited similar progressive and profound declines in ERG amplitudes. However, in some of the dogs treated with rhTPP1 there were substantial delays in the appearance and progression of PLR deficits compared with untreated or vehicle treated affected dogs. These findings indicate that CSF administration of TPP1 can attenuate functional impairment of neural pathways involved in mediating the PLR but does not prevent loss of retinal responses detectable with ERG.

PMID: 24954537 [PubMed - indexed for MEDLINE]

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Enzyme replacement therapy delays pupillary light reflex deficits in a canine model of late infantile neuronal ceroid lipofuscinosis.

Exp Eye Res. 2014 Aug;125:164-72

Authors: Whiting RE, Narfström K, Yao G, Pearce JW, Coates JR, Castaner LJ, Jensen CA, Dougherty BN, Vuillemenot BR, Kennedy D, O'Neill CA, Katz ML

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Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS: safety, pharmacokinetics, and distribution.

Toxicol Appl Pharmacol. 2014 May 15;277(1):49-57

Authors: Vuillemenot BR, Kennedy D, Reed RP, Boyd RB, Butt MT, Musson DG, Keve S, Cahayag R, Tsuruda LS, O'Neill CA

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Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS: safety, pharmacokinetics, and distribution.

Toxicol Appl Pharmacol. 2014 May 15;277(1):49-57

Authors: Vuillemenot BR, Kennedy D, Reed RP, Boyd RB, Butt MT, Musson DG, Keve S, Cahayag R, Tsuruda LS, O'Neill CA

Abstract
CLN2 disease is caused by deficiency in tripeptidyl peptidase-1 (TPP1), leading to neurodegeneration and death. The safety, pharmacokinetics (PK), and CNS distribution of recombinant human TPP1 (rhTPP1) were characterized following a single intracerebroventricular (ICV) or intrathecal-lumbar (IT-L) infusion to cynomolgus monkeys. Animals received 0, 5, 14, or 20mg rhTPP1, ICV, or 14 mg IT-L, in artificial cerebrospinal fluid (aCSF) vehicle. Plasma and CSF were collected for PK analysis. Necropsies occurred at 3, 7, and 14 days post-infusion. CNS tissues were sampled for rhTPP1 distribution. TPP1 infusion was well tolerated and without effect on clinical observations or ECG. A mild increase in CSF white blood cells (WBCs) was detected transiently after ICV infusion. Isolated histological changes related to catheter placement and infusion were observed in ICV treated animals, including vehicle controls. The CSF and plasma exposure profiles were equivalent between animals that received an ICV or IT-L infusion. TPP1 levels peaked at the end of infusion, at which point the enzyme was present in plasma at 0.3% to 0.5% of CSF levels. TPP1 was detected in brain tissues with half-lives of 3-14 days. CNS distribution between ICV and IT-L administration was similar, although ICV resulted in distribution to deep brain structures including the thalamus, midbrain, and striatum. Direct CNS infusion of rhTPP1 was well tolerated with no drug related safety findings. The favorable nonclinical profile of ICV rhTPP1 supports the treatment of CLN2 by direct administration to the CNS.

PMID: 24642058 [PubMed - indexed for MEDLINE]

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Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS: safety, pharmacokinetics, and distribution.

Toxicol Appl Pharmacol. 2014 May 15;277(1):49-57

Authors: Vuillemenot BR, Kennedy D, Reed RP, Boyd RB, Butt MT, Musson DG, Keve S, Cahayag R, Tsuruda LS, O'Neill CA

2013

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Corneal inflammation is inhibited by the LFA-1 antagonist, lifitegrast (SAR 1118).

J Ocul Pharmacol Ther. 2013 May;29(4):395-402

Authors: Sun Y, Zhang R, Gadek TR, O'Neill CA, Pearlman E

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Corneal inflammation is inhibited by the LFA-1 antagonist, lifitegrast (SAR 1118).

J Ocul Pharmacol Ther. 2013 May;29(4):395-402

Authors: Sun Y, Zhang R, Gadek TR, O'Neill CA, Pearlman E

Abstract
PURPOSE: Sterile corneal infiltrates can cause pain, blurred vision, and ocular discomfort in silicone hydrogel contact-lens users. The current study investigates the potential for the synthetic lymphocyte functional antigen-1 (LFA-1) antagonist lifitegrast (SAR 1118) to block corneal inflammation using a murine model.
METHODS: The role of LFA-1 (CD11a/CD18) was examined either in CD18(-/-) mice, by intraperitoneal injection of anti-CD11a, or by topical application of lifitegrast. Corneal inflammation was induced by epithelial abrasion and exposure to either tobramycin-killed Pseudomonas aeruginosa or Staphylococcus aureus in the presence of a 2-mm-diameter punch from a silicone hydrogel contact lens. After 24 h, corneal thickness and haze were examined by in vivo confocal microscopy, and neutrophil recruitment to the corneal stroma was detected by immunohistochemistry.
RESULTS: Neutrophil recruitment to the corneal stroma and development of stromal haze were significantly impaired in CD18(-/-) mice or after injection of anti-CD11a. Topical lifitegrast also inhibited P. aeruginosa- and S. aureus-induced inflammation, with the optimal application being a 1% solution applied either 2 or 3 times prior.
CONCLUSION: As LFA-1-dependent neutrophil recruitment to the corneal stroma can be blocked by topical lifitegrast, this reagent could be used in combination with antibiotics to prevent leukocyte infiltration to the corneal stroma in association with contact-lens wear.

PMID: 23215542 [PubMed - indexed for MEDLINE]

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Corneal inflammation is inhibited by the LFA-1 antagonist, lifitegrast (SAR 1118).

J Ocul Pharmacol Ther. 2013 May;29(4):395-402

Authors: Sun Y, Zhang R, Gadek TR, O'Neill CA, Pearlman E

2012

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Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia.

Am J Hum Genet. 2012 Dec 7;91(6):1108-14

Authors: Lorget F, Kaci N, Peng J, Benoist-Lasselin C, Mugniery E, Oppeneer T, Wendt DJ, Bell SM, Bullens S, Bunting S, Tsuruda LS, O'Neill CA, Di Rocco F, Munnich A, Legeai-Mallet L

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Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia.

Am J Hum Genet. 2012 Dec 7;91(6):1108-14

Authors: Lorget F, Kaci N, Peng J, Benoist-Lasselin C, Mugniery E, Oppeneer T, Wendt DJ, Bell SM, Bullens S, Bunting S, Tsuruda LS, O'Neill CA, Di Rocco F, Munnich A, Legeai-Mallet L

Abstract
Achondroplasia (ACH), the most common form of dwarfism, is an inherited autosomal-dominant chondrodysplasia caused by a gain-of-function mutation in fibroblast-growth-factor-receptor 3 (FGFR3). C-type natriuretic peptide (CNP) antagonizes FGFR3 downstream signaling by inhibiting the pathway of mitogen-activated protein kinase (MAPK). Here, we report the pharmacological activity of a 39 amino acid CNP analog (BMN 111) with an extended plasma half-life due to its resistance to neutral-endopeptidase (NEP) digestion. In ACH human growth-plate chondrocytes, we demonstrated a decrease in the phosphorylation of extracellular-signal-regulated kinases 1 and 2, confirming that this CNP analog inhibits fibroblast-growth-factor-mediated MAPK activation. Concomitantly, we analyzed the phenotype of Fgfr3(Y367C/+) mice and showed the presence of ACH-related clinical features in this mouse model. We found that in Fgfr3(Y367C/+) mice, treatment with this CNP analog led to a significant recovery of bone growth. We observed an increase in the axial and appendicular skeleton lengths, and improvements in dwarfism-related clinical features included flattening of the skull, reduced crossbite, straightening of the tibias and femurs, and correction of the growth-plate defect. Thus, our results provide the proof of concept that BMN 111, a NEP-resistant CNP analog, might benefit individuals with ACH and hypochondroplasia.

PMID: 23200862 [PubMed - indexed for MEDLINE]

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Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia.

Am J Hum Genet. 2012 Dec 7;91(6):1108-14

Authors: Lorget F, Kaci N, Peng J, Benoist-Lasselin C, Mugniery E, Oppeneer T, Wendt DJ, Bell SM, Bullens S, Bunting S, Tsuruda LS, O'Neill CA, Di Rocco F, Munnich A, Legeai-Mallet L

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Intrathecal recombinant human 4-sulfatase reduces accumulation of glycosaminoglycans in dura of mucopolysaccharidosis VI cats.

Pediatr Res. 2012 Jan;71(1):39-45

Authors: Auclair D, Finnie J, Walkley SU, White J, Nielsen T, Fuller M, Cheng A, O'Neill CA, Hopwood JJ

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Intrathecal recombinant human 4-sulfatase reduces accumulation of glycosaminoglycans in dura of mucopolysaccharidosis VI cats.

Pediatr Res. 2012 Jan;71(1):39-45

Authors: Auclair D, Finnie J, Walkley SU, White J, Nielsen T, Fuller M, Cheng A, O'Neill CA, Hopwood JJ

Abstract
INTRODUCTION: Mucopolysaccharidosis VI (MPS-VI) is caused by a deficiency in N-acetylgalactosamine-4-sulfatase activity, resulting in lysosomal accumulation of partially degraded glycosaminoglycans (GAGs). Compressive myelopathy in early-onset MPS-VI patients has been partly attributed to thickening of the dura mater following engorgement with GAG. In this study, we therefore tested whether the dural abnormalities could be prevented in a feline model of the disorder.
RESULTS: All intrathecal injections (IT-INJs) were well tolerated. MPS-VI cats treated with IT-INJ of recombinant human N-acetylgalactosamine-4-sulfatase (rhASB) exhibited reduced vacuolation in the dural fibroblasts, diminished levels of sulfated-N-acetylhexosamine (HNAc(+S)) in the cerebrospinal fluid (CSF) and no hind-limb paresis. Serum anti-rhASB antibodies remained low in MPS-VI cats treated with intravenous enzyme replacement therapy (IV-ERT) and increased slightly in normal cats treated with IT-INJ of rhASB alone. Anti-rhASB antibodies in CSF remained undetectable.
DISCUSSION: These data indicate that repeated IT-INJ of rhASB can safely prevent GAG storage in MPS-VI dura.
METHODS: Cats were assigned to three groups: (i) receiving weekly IV-ERT of rhASB from birth plus six monthly IT-INJs of rhASB from age 2 months; (ii) receiving six monthly IT-INJs of vehicle; or (iii) untreated. Additional normal cats received five fortnightly IT-INJs of rhASB or vehicle alone.

PMID: 22289849 [PubMed - indexed for MEDLINE]

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Intrathecal recombinant human 4-sulfatase reduces accumulation of glycosaminoglycans in dura of mucopolysaccharidosis VI cats.

Pediatr Res. 2012 Jan;71(1):39-45

Authors: Auclair D, Finnie J, Walkley SU, White J, Nielsen T, Fuller M, Cheng A, O'Neill CA, Hopwood JJ

2011

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Intrathecal tripeptidyl-peptidase 1 reduces lysosomal storage in a canine model of late infantile neuronal ceroid lipofuscinosis.

Mol Genet Metab. 2011 Nov;104(3):325-37

Authors: Vuillemenot BR, Katz ML, Coates JR, Kennedy D, Tiger P, Kanazono S, Lobel P, Sohar I, Xu S, Cahayag R, Keve S, Koren E, Bunting S, Tsuruda LS, O'Neill CA

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Intrathecal tripeptidyl-peptidase 1 reduces lysosomal storage in a canine model of late infantile neuronal ceroid lipofuscinosis.

Mol Genet Metab. 2011 Nov;104(3):325-37

Authors: Vuillemenot BR, Katz ML, Coates JR, Kennedy D, Tiger P, Kanazono S, Lobel P, Sohar I, Xu S, Cahayag R, Keve S, Koren E, Bunting S, Tsuruda LS, O'Neill CA

Abstract
Late infantile neuronal ceroid lipofuscinosis (LINCL) is caused by mutations in the gene encoding tripeptidyl-peptidase 1 (TPP1). LINCL patients accumulate lysosomal storage materials in the CNS accompanied by neurodegeneration, blindness, and functional decline. Dachshunds homozygous for a null mutation in the TPP1 gene recapitulate many symptoms of the human disease. The objectives of this study were to determine whether intrathecal (IT) TPP1 treatment attenuates storage accumulation and functional decline in TPP1-/- Dachshunds and to characterize the CNS distribution of TPP1 activity. TPP1 was administered to one TPP1-/- and one homozygous wild-type (WT) dog. An additional TPP1-/- and WT dog received vehicle. Four IT administrations of 32 mg TPP1 formulated in 2.3 mL of artificial cerebrospinal fluid (aCSF) or vehicle were administered monthly via the cerebellomedullary cistern from four to seven months of age. Functional decline was assessed by physical and neurological examinations, electrophysiology, and T-maze performance. Neural tissues were collected 48 h after the fourth administration and analyzed for TPP1 activity and autofluorescent storage material. TPP1 was distributed at greater than WT levels in many areas of the CNS of the TPP1-/- dog administered TPP1. The amount of autofluorescent storage was decreased in this dog relative to the vehicle-treated affected control. No improvement in overall function was observed in this dog compared to the vehicle-treated TPP1-/- littermate control. These results demonstrate for the first time in a large animal model of LINCL widespread delivery of biochemically active TPP1 to the brain after IT administration along with a decrease in lysosomal storage material. Further studies with this model will be necessary to optimize the dosing route and regimen to attenuate functional decline.

PMID: 21784683 [PubMed - indexed for MEDLINE]

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Intrathecal tripeptidyl-peptidase 1 reduces lysosomal storage in a canine model of late infantile neuronal ceroid lipofuscinosis.

Mol Genet Metab. 2011 Nov;104(3):325-37

Authors: Vuillemenot BR, Katz ML, Coates JR, Kennedy D, Tiger P, Kanazono S, Lobel P, Sohar I, Xu S, Cahayag R, Keve S, Koren E, Bunting S, Tsuruda LS, O'Neill CA

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Bi-modal dose-dependent cardiac response to tetrahydrobiopterin in pressure-overload induced hypertrophy and heart failure.

J Mol Cell Cardiol. 2011 Oct;51(4):564-9

Authors: Moens AL, Ketner EA, Takimoto E, Schmidt TS, O'Neill CA, Wolin MS, Alp NJ, Channon KM, Kass DA

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Bi-modal dose-dependent cardiac response to tetrahydrobiopterin in pressure-overload induced hypertrophy and heart failure.

J Mol Cell Cardiol. 2011 Oct;51(4):564-9

Authors: Moens AL, Ketner EA, Takimoto E, Schmidt TS, O'Neill CA, Wolin MS, Alp NJ, Channon KM, Kass DA

Abstract
The exogenous administration of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase (NOS), has been shown to reduce left ventricular hypertrophy, fibrosis, and cardiac dysfunction in mice with pre-established heart disease induced by pressure-overload. In this setting, BH4 re-coupled endothelial NOS (eNOS), with subsequent reduction of NOS-dependent oxidative stress and reversal of maladaptive remodeling. However, recent studies suggest the effective BH4 dosing may be narrower than previously thought, potentially due to its oxidation upon oral consumption. Accordingly, we assessed the dose response of daily oral synthetic sapropterin dihydrochloride (6-R-l-erythro-5,6,7,8-tetrahydrobiopterin, 6R-BH4) on pre-established pressure-overload cardiac disease. Mice (n=64) were administered 0-400mg/kg/d BH4 by ingesting small pre-made pellets (consumed over 15-30 min). In a dose range of 36-200mg/kg/d, 6R-BH4 suppressed cardiac chamber remodeling, hypertrophy, fibrosis, and oxidative stress with pressure-overload. However, at both lower and higher doses, BH4 had less or no ameliorative effects. The effective doses correlated with a higher myocardial BH4/BH2 ratio. However, BH2 rose linearly with dose, and at the 400mg/kg/d, this lowered the BH4/BH2 ratio back toward control. These results expose a potential limitation for the clinical use of BH4, as variability of cellular redox and perhaps heart disease could produce a variable therapeutic window among individuals. This article is part of a special issue entitled ''Key Signaling Molecules in Hypertrophy and Heart Failure.''

PMID: 21645517 [PubMed - indexed for MEDLINE]

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Bi-modal dose-dependent cardiac response to tetrahydrobiopterin in pressure-overload induced hypertrophy and heart failure.

J Mol Cell Cardiol. 2011 Oct;51(4):564-9

Authors: Moens AL, Ketner EA, Takimoto E, Schmidt TS, O'Neill CA, Wolin MS, Alp NJ, Channon KM, Kass DA

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Biodistribution and pharmacodynamics of recombinant human alpha-L-iduronidase (rhIDU) in mucopolysaccharidosis type I-affected cats following multiple intrathecal administrations.

Mol Genet Metab. 2011 Jul;103(3):268-74

Authors: Vite CH, Wang P, Patel RT, Walton RM, Walkley SU, Sellers RS, Ellinwood NM, Cheng AS, White JT, O'Neill CA, Haskins M

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Biodistribution and pharmacodynamics of recombinant human alpha-L-iduronidase (rhIDU) in mucopolysaccharidosis type I-affected cats following multiple intrathecal administrations.

Mol Genet Metab. 2011 Jul;103(3):268-74

Authors: Vite CH, Wang P, Patel RT, Walton RM, Walkley SU, Sellers RS, Ellinwood NM, Cheng AS, White JT, O'Neill CA, Haskins M

Abstract
The storage disorder mucopolysaccharidosis type I (MPS I) is caused by a deficiency in lysosomal α-L-iduronidase activity. The inability to degrade glycosaminoglycans (GAG) results in lysosomal accumulation and widespread tissue lesions. Many symptoms of MPS I are amenable to treatment with recombinant human α-L-iduronidase (rhIDU), however, peripherally administered rhIDU does not cross the blood-brain barrier and has no beneficial effects in the central nervous system (CNS). A feline model of MPS I was used to evaluate the CNS effects of rhIDU following repeated intrathecal (IT) administration. Twelve animals were randomized into four groups based on the time of euthanasia and tissue evaluation following three repeat IT administrations of 0.1 mg/kg rhIDU or placebo on Study Days 1, 4 or 5, and 9. Two days after the final IT injection, the mean tissue α-L-iduronidase (IDU) activity in the brains of the two treated animals were approximately 3-times higher (50.1 and 54.9 U/mg protein) than the activity found in normal cat brains (mean of 18.3 U/mg), and remained higher than untreated MPSI brain at 1 month (2.4 and 4.1 U/mg protein) before returning to near-baseline levels after 2 months. This activity corresponded with decreased brain GAG concentrations after 2 days (1.4 and 2.0 μg/mg) and 1 month (0.9 and 1.1 μg/mg) which approached levels observed in normal animals (0.7 μg/mg). Attenuation of GAG, gangliosides GM2 and GM3, and cholesterol reaccumulation was identified at both two days and one month following final IT injection. No adverse effects attributable to IT rhIDU administration were observed. IT rhIDU may be an effective means for providing enzyme replacement therapy for the central manifestations of MPS I.

PMID: 21482164 [PubMed - indexed for MEDLINE]

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Biodistribution and pharmacodynamics of recombinant human alpha-L-iduronidase (rhIDU) in mucopolysaccharidosis type I-affected cats following multiple intrathecal administrations.

Mol Genet Metab. 2011 Jul;103(3):268-74

Authors: Vite CH, Wang P, Patel RT, Walton RM, Walkley SU, Sellers RS, Ellinwood NM, Cheng AS, White JT, O'Neill CA, Haskins M

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Safety and pharmacokinetics of a novel lymphocyte function-associated antigen-1 antagonist ophthalmic solution (SAR 1118) in healthy adults.

J Ocul Pharmacol Ther. 2011 Feb;27(1):99-104

Authors: Semba CP, Swearingen D, Smith VL, Newman MS, O'Neill CA, Burnier JP, Haughey DB, Gadek TR

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Safety and pharmacokinetics of a novel lymphocyte function-associated antigen-1 antagonist ophthalmic solution (SAR 1118) in healthy adults.

J Ocul Pharmacol Ther. 2011 Feb;27(1):99-104

Authors: Semba CP, Swearingen D, Smith VL, Newman MS, O'Neill CA, Burnier JP, Haughey DB, Gadek TR

Abstract
PURPOSE: To investigate the safety, tolerability, and pharmacokinetics (PKs) of topical SAR 1118 Ophthalmic Solution in healthy adults. SAR 1118 is an investigational small molecule lymphocyte function-associated antigen-1 (LFA-1; CD11a/CD18; αLβ2) antagonist that inhibits LFA-1 binding to intercellular adhesion molecule-1 (ICAM-1; CD54) targeting T-cell-mediated inflammation.
METHODS: A randomized, double-masked, placebo-controlled, dose-escalation study of SAR 1118 was performed in 4 cohorts with 7 randomized subjects per cohort (2 placebo: 5 active drug subjects; 0.1%, 0.3%, 1.0%, 5.0%) in 28 healthy adults. Dosing was divided into 3 periods each separated by a 72-h treatment-free observation: once-daily (QD) × 1, twice-daily (BID) × 10, and thrice-daily (TID) × 10 days. Data obtained at the beginning and end of each period included: slit-lamp, best-corrected visual acuity (BCVA), Schirmer tear test (STT) without anesthesia, tear film break-up time (TBUT), intraocular pressure (IOP), and tear/plasma samples for PK analysis.
RESULTS: All subjects completed the study; there were no tolerability issues or missed treatments (total, 1,428 administered doses). No serious ocular or nonocular adverse events (AEs) occurred over 1,148 subject study days (41 days/subject) and no significant abnormalities were identified on ocular exam. There were 38 ocular AEs (N = 11 subjects) and 21 nonocular AEs (N = 11 subjects). Most AEs were mild in severity and occurred in the 0.3% and placebo groups. No changes were observed in CD3, CD4, and CD8 blood lymphocyte counts. Tear PK profiles support a QD/BID dosing schedule. Plasma levels of SAR 1118 in the 0.1% and 0.3% groups were below level of quantitation (BLQ; <0.50  ng/mL) at all time points and transiently detected within the first 5 min to ∼1  h following administration in the 1.0% and 5.0% groups.
CONCLUSION: SAR 1118 Ophthalmic Solution appears safe and well-tolerated up to 5.0% TID in healthy adult subjects. PK analysis shows adequate ocular exposure with minimal systemic exposure.

PMID: 20334535 [PubMed - indexed for MEDLINE]

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Safety and pharmacokinetics of a novel lymphocyte function-associated antigen-1 antagonist ophthalmic solution (SAR 1118) in healthy adults.

J Ocul Pharmacol Ther. 2011 Feb;27(1):99-104

Authors: Semba CP, Swearingen D, Smith VL, Newman MS, O'Neill CA, Burnier JP, Haughey DB, Gadek TR

2010

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Delivery of SAR 1118 to the retina via ophthalmic drops and its effectiveness in a rat streptozotocin (STZ) model of diabetic retinopathy (DR).

Invest Ophthalmol Vis Sci. 2010 Oct;51(10):5198-204

Authors: Rao VR, Prescott E, Shelke NB, Trivedi R, Thomas P, Struble C, Gadek T, O'Neill CA, Kompella UB

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Delivery of SAR 1118 to the retina via ophthalmic drops and its effectiveness in a rat streptozotocin (STZ) model of diabetic retinopathy (DR).

Invest Ophthalmol Vis Sci. 2010 Oct;51(10):5198-204

Authors: Rao VR, Prescott E, Shelke NB, Trivedi R, Thomas P, Struble C, Gadek T, O'Neill CA, Kompella UB

Abstract
PURPOSE: To determine the pharmacokinetics of SAR 1118, a small-molecule antagonist of leukocyte function-associated antigen (LFA)-1, after administration of ophthalmic drops in normal rats, and to determine its pharmacologic activity by assessing the inhibition of retinal leukostasis and vascular leakiness in a streptozotocin (STZ)-induced diabetic retinopathy model.
METHODS: The ocular pharmacokinetics of SAR 1118 were studied in rats after a single topical dose of (14)C-SAR 1118 (1 mg/eye; 40 μCi; 15.5 μL). SAR 1118 concentration time profiles in plasma and ocular tissues were quantified by liquid scintillation counting (LSC). The pharmacologic activity of SAR 1118 eye drops administered thrice daily for 2 months at 1% (0.3 mg/eye/d) and 5% (1.5 mg/eye/d) was assessed in an STZ-induced diabetic rat model by determining retinal leukostasis and blood-retinal barrier breakdown. Diabetic rats treated with periocularly administered celecoxib microparticles served as the positive control, and vehicle-treated rats served as the negative control.
RESULTS: A single dose of 6.5% (14)C-radiolabeled SAR 1118 ophthalmic drops delivered retinal drug levels greater than 1 μM in less than 30 minutes and sustained levels greater than 100 nM for 8 hours. SAR 1118 eye drops significantly reduced leukostasis and blood-retinal barrier breakdown in a dose-dependent manner.
CONCLUSIONS: SAR 1118 ophthalmic drops administered thrice daily deliver therapeutic levels of SAR 1118 in the retina and can alleviate the retinal complications associated with diabetes.

PMID: 20445119 [PubMed - indexed for MEDLINE]

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Delivery of SAR 1118 to the retina via ophthalmic drops and its effectiveness in a rat streptozotocin (STZ) model of diabetic retinopathy (DR).

Invest Ophthalmol Vis Sci. 2010 Oct;51(10):5198-204

Authors: Rao VR, Prescott E, Shelke NB, Trivedi R, Thomas P, Struble C, Gadek T, O'Neill CA, Kompella UB

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Tetrahydrobiopterin supplementation reduces atherosclerosis and vascular inflammation in apolipoprotein E-knockout mice.

Clin Sci (Lond). 2010 Aug;119(3):131-42

Authors: Schmidt TS, McNeill E, Douglas G, Crabtree MJ, Hale AB, Khoo J, O'Neill CA, Cheng A, Channon KM, Alp NJ

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Tetrahydrobiopterin supplementation reduces atherosclerosis and vascular inflammation in apolipoprotein E-knockout mice.

Clin Sci (Lond). 2010 Aug;119(3):131-42

Authors: Schmidt TS, McNeill E, Douglas G, Crabtree MJ, Hale AB, Khoo J, O'Neill CA, Cheng A, Channon KM, Alp NJ

Abstract
BH4 (tetrahydrobiopterin) supplementation improves endothelial function in models of vascular disease by maintaining eNOS (endothelial nitric oxide synthase) coupling and NO (nitric oxide) bioavailability. However, the cellular mechanisms through which enhanced endothelial function leads to reduced atherosclerosis remain unclear. We have used a pharmaceutical BH4 formulation to investigate the effects of BH4 supplementation on atherosclerosis progression in ApoE-KO (apolipoprotein E-knockout) mice. Single oral dose pharmacokinetic studies revealed rapid BH4 uptake into plasma and organs. Plasma BH4 levels returned to baseline by 8 h after oral dosing, but remained markedly increased in aorta at 24 h. Daily oral BH4 supplementation in ApoE-KO mice from 8 weeks of age, for a period of 8 or 12 weeks, had no effect on plasma lipids or haemodynamic parameters, but significantly reduced aortic root atherosclerosis compared with placebo-treated animals. BH4 supplementation significantly reduced VCAM-1 (vascular cell adhesion molecule 1) mRNA levels in aortic endothelial cells, markedly reduced the infiltration of T-cells, macrophages and monocytes into plaques, and reduced T-cell infiltration in the adjacent adventitia, but importantly had no effect on circulating leucocytes. GCH (GTP cyclohydrolase I)-transgenic mice, with a specific increase in endothelial BH4 levels, exhibited a similar reduction in vascular immune cell infiltration compared with BH4-deficient controls, suggesting that BH4 reduces vascular inflammation via endothelial cell signalling. In conclusion, BH4 supplementation reduces vascular immune cell infiltration in atherosclerosis and may therefore be a rational therapeutic approach to reduce the progression of atherosclerosis.

PMID: 20337596 [PubMed - indexed for MEDLINE]

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Tetrahydrobiopterin supplementation reduces atherosclerosis and vascular inflammation in apolipoprotein E-knockout mice.

Clin Sci (Lond). 2010 Aug;119(3):131-42

Authors: Schmidt TS, McNeill E, Douglas G, Crabtree MJ, Hale AB, Khoo J, O'Neill CA, Cheng A, Channon KM, Alp NJ

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Repeated intrathecal injections of recombinant human 4-sulphatase remove dural storage in mature mucopolysaccharidosis VI cats primed with a short-course tolerisation regimen.

Mol Genet Metab. 2010 Feb;99(2):132-41

Authors: Auclair D, Finnie J, White J, Nielsen T, Fuller M, Kakkis E, Cheng A, O'Neill CA, Hopwood JJ

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Repeated intrathecal injections of recombinant human 4-sulphatase remove dural storage in mature mucopolysaccharidosis VI cats primed with a short-course tolerisation regimen.

Mol Genet Metab. 2010 Feb;99(2):132-41

Authors: Auclair D, Finnie J, White J, Nielsen T, Fuller M, Kakkis E, Cheng A, O'Neill CA, Hopwood JJ

Abstract
All MPS-VI cats treated thus far with weekly intravenous enzyme replacement therapy (IV ERT) with recombinant human N-acetylgalactosamine-4-sulphatase (rhASB) from 3 months of age onwards developed circulating anti-rhASB antibodies. In view of this, the possibility of inducing immune tolerance by using a short-course tolerisation regimen was tested. Starting at 4 months of age, MPS-VI (n=5) and unaffected cats (n=2) received cyclosporine and azathioprine over a 22-day period plus weekly IV ERT with 0.1mg/kg rhASB. After a 4-week resting period, these cats were administered weekly IV ERT with 1mg/kg rhASB until 11 or 17 months of age. Four unaffected cats (n=4) received weekly IV ERT only. Health, growth and seroconversion were regularly monitored. Four out of five MPS-VI cats tolerated rhASB well, as indicated by negligible or low antibody titres and absence of hypersensitivity reactions. One MPS-VI cat exhibited elevated antibody titres and hypersensitivity reactions during some IV treatments. The two unaffected cats that received the tolerisation regimen remained seronegative, however, only half of the unaffected cats not submitted to this regimen seroconverted. Only minor side-effects were attributed to the short-course of cyclosporine and azathioprine. Two MPS-VI cats also well-tolerated four weekly intrathecal injections of rhASB and consequently exhibited less oligosaccharide fragments in cerebrospinal fluid and less vacuolation within their dura mater. These data indicate that a relatively high rate of immunotolerance towards rhASB can be achieved in MPS-VI cats with a short-course tolerisation regimen ultimately permitting removal of lysosomal storage within the dura mater with the use of intrathecal therapy.

PMID: 19896877 [PubMed - indexed for MEDLINE]

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Authors: Auclair D, Finnie J, White J, Nielsen T, Fuller M, Kakkis E, Cheng A, O'Neill CA, Hopwood JJ