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

Vuillemenot, Brian R.; Kennedy, Derek; Cooper, Jonathan D.; Wong, Andrew; Sri, Sarmi; Doeleman, Thom; Katz, Martin L.; Coates, Joan R.; Johnson, Gayle C.; Reed, Randall P.; Adams, Eric; Butt, Mark T.; Musson, Donald G.; Henshaw, Joshua; Keve, Steve; Cahayag, Rhea; Tsuruda, Laurie S.; O’Neill, Charles

doi:10.1016/j.ymgme.2014.09.004

Cited by 53 publications

(70 citation statements)

References 34 publications

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“…To date, systematic therapeutic interventions for canine NCLs have only been evaluated for the CLN8 disease in English Setters(Siakotos et al, 2001) and for the CLN2 disease in Miniature Longhaired Dachshunds (Katz et al, 2014; Katz et al, 2017; Katz et al, 2015; Tracy et al, 2016a; Vuillemenot et al, 2011; Vuillemenot et al, 2015; Whiting et al, 2016; Whiting et al, 2014). It has been reported that a major component of the storage material that accumulates in a number of the NCLs is subunit c protein, a subunit of mitochondrial ATP synthase (Palmer et al, 2013; Palmer et al, 1989) It was discovered that both the form of the subunit c protein stored in some of the NCLs and the form present in mitochondria from normal animals contains a trimethylated lysine (TML) residue (Katz et al, 1994b; Katz et al, 1995b; Katz and Gerhardt, 1992; Katz and Rodrigues, 1991; Katz et al, 1997).…”

Section: Investigation Of Therapeutic Interventions For Treating Tmentioning

confidence: 99%

Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions

Katz

Rustad²,

Robinson

et al. 2017

Neurobiology of Disease

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The neuronal ceroid lipofuscinoses (NCLs) are devastating inherited progressive neurodegenerative diseases, with most forms having a childhood onset of clinical signs. The NCLs are characterized by progressive cognitive and motor decline, vision loss, seizures, respiratory and swallowing impairment, and ultimately premature death. Different forms of NCL result from mutations in at least 13 genes. The clinical signs of some forms overlap significantly, so genetic testing is the only way to definitively determine which form an individual patient suffers from. At present, an effective treatment is available for only one form of NCL. Evidence of NCL has been documented in over 20 canine breeds and in mixed-breed dogs. To date, 12 mutations in 8 different genes orthologous to the human NCL genes have been found to underlie NCL in a variety of dog breeds. A Dachshund model with a null mutation in one of these genes is being utilized to investigate potential therapeutic interventions, including enzyme replacement and gene therapies. Demonstration of the efficacy of enzyme replacement therapy in this model led to successful completion of human clinical trials of this treatment. Further research into the other canine NCLs, with in-depth characterization and understanding of the disease processes, will likely lead to the development of successful therapeutic interventions for additional forms of NCL, for both human patients and animals with these disorders.

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Section: Investigation Of Therapeutic Interventions For Treating Tmentioning

confidence: 99%

Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions

Katz

Rustad²,

Robinson

et al. 2017

Neurobiology of Disease

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“…Sections of the tissues were cut with a cryostat at a thickness of 8 μm and mounted on Superfrost Plus slides (Fisher Scientific, Fairlawn, NJ) in 170 mM sodium cacodylate. The sections were examined and photographed using fluorescence microscopy as previously described [27]. For electron microscopic examination, the tissue samples were fixed in 2.5% glutaraldehyde in 100 mM sodium cacodylate, pH 7.4.…”

Section: Fluorescence and Electron Microscopy And Immunohistopathologymentioning

confidence: 99%

“…These canine models can be used to study disease mechanisms or to evaluate therapeutic interventions. For instance, a research colony founded from dogs with NCL due to a rare TPP1 mutation [11] provided subjects for preclinical trials that established the efficacy of enzyme replacement therapy for TPP1-deficient dogs [27][28][29]. This helped pave the way for an ongoing clinical trial with enzyme replacement therapy for TPP1-deficient children that appears to be slowing their disease progression (https://www.clinicaltrials.gov/ct2/show/NCT01907087).…”

Section: Introductionmentioning

confidence: 99%

Golden Retriever dogs with neuronal ceroid lipofuscinosis have a two-base-pair deletion and frameshift in CLN5

Gilliam

Kolicheski

Johnson

et al. 2015

Molecular Genetics and Metabolism

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We studied a recessive, progressive neurodegenerative disease occurring in Golden Retriever siblings with an onset of signs at 15 months of age. As the disease progressed these signs included ataxia, anxiety, pacing and circling, tremors, aggression, visual impairment and localized and generalized seizures. A whole genome sequence, generated with DNA from one affected dog, contained a plausibly causal homozygous mutation: CLN5:c.934_935delAG. This mutation was predicted to produce a frameshift and premature termination codon and encode a protein variant, CLN5:p.E312Vfs*6, which would lack 39 C-terminal amino acids. Eighteen DNA samples from the Golden Retriever family members were genotyped at CLN5:c.934_935delAG. Three clinically affected dogs were homozygous for the deletion allele; whereas, the clinically normal family members were either heterozygotes (n = 11) or homozygous for the reference allele (n = 4). Among archived Golden Retrievers DNA samples with incomplete clinical records that were also genotyped at the CLN5:c.934_935delAG variant, 1053 of 1062 were homozygous for the reference allele, 8 were heterozygotes and one was a deletion-allele homozygote. When contacted, the owner of this homozygote indicated that their dog had been euthanized because of a neurologic disease that progressed similarly to that of the affected Golden Retriever siblings. We have collected and stored semen from a heterozygous Golden Retriever, thereby preserving an opportunity for us or others to establish a colony of CLN5-deficient dogs.

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“…In all of these investigations, widespread enzyme distribution and a reduction in pathological lesions in the central nervous system were reported, enabling improvements in clinical function. Finally, in the Dachshund dog model of late-infantile neuronal ceroid lipofuscinosis (Batten's disease), a combination of ventricular and intrathecal lumbar injections (or where cannula patency was an issue, cisternal infusion), mediated a delay in the onset of clinical symptoms and prolonged lifespan [16,42]. The ventricular route of administering recombinant enzyme is currently under investigation in a Phase I/II trial in children with Batten's disease (www.clinicaltrials.gov; NCT#01907087).…”

Section: Discussionmentioning

confidence: 99%

Determination of the role of injection site on the efficacy of intra-CSF enzyme replacement therapy in MPS IIIA mice

Beard

Luck

Hassiotis

et al. 2015

Molecular Genetics and Metabolism

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

Cited by 53 publications

References 34 publications

Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions

Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions

Golden Retriever dogs with neuronal ceroid lipofuscinosis have a two-base-pair deletion and frameshift in CLN5

Determination of the role of injection site on the efficacy of intra-CSF enzyme replacement therapy in MPS IIIA mice

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