Neuroprotection and lifespan extension in Ppt1−/− mice by NtBuHA: therapeutic implications for INCL

Sarkar, Chinmoy; Chandra, Goutam; Peng, Shiyong; Zhang, Zhongjian; Liu, Aiyi; Mukherjee, Anil B.

doi:10.1038/nn.3526

Cited by 67 publications

(93 citation statements)

References 49 publications

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“…Thus, non-toxic, thioesterase-mimetic small molecules may provide a more efficacious therapeutic strategy for INCL patients as these molecules would readily cross the BBB even when its integrity is restored. Towards this goal, we recently identified a small molecule, N-tert-(Butyl)-hydroxylamine, which protected neurons, and modestly extended lifespan in Ppt1 −/− mice 44 .…”

Section: Discussionmentioning

confidence: 99%

Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study

Levin

Baker

Zein

et al. 2014

The Lancet Neurology

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Summary Background Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative lysosomal storage disease caused by mutations in the CLN1 gene encoding palmitoyl-protein thioesterase-1 (PPT1). PPT1-deficiency causes lysosomal ceroid accumulation leading to INCL pathogenesis. Previously, we reported that phosphocysteamine and N-acetylcysteine mediated ceroid depletion in cultured cells from INCL patients. We conducted a pilot study to determine whether a combination of cysteamine bitartrate and N-acetylcysteine is beneficial for these patients. Methods Patients (6-month to 3-years old) with any combination of 2 of the 7 most lethal PPT1 mutations were admitted. All patients were recruited from physician referrals and the PPT1 mutations were analyzed prior to admission. Patients were evaluated by electroretinography(ERG), brain MRI and MRS, electroencephalography (EEG), and electron microscopic analyses of leukocytes for granular osmiophilic deposits (GRODs). Patients received oral cysteamine bitartrate (60mg/kg/day) and N-acetylcysteine (60mg/kg/day) and were evaluated every 6 to 12 months until they showed isoelectric EEG attesting to a vegetative state or were too sick to travel. Outcomes were compared with the reported INCL natural history. In two cases, the disease progression was compared with that of a sibling who was above the age limit for inclusion into the protocol. Findings Between March, 2001, and June, 2011, we recruited 10 children with INCL but one was lost to follow-up after the first visit. Thus, a total of 9 patients (5 females and 4 males) were studied. At the first follow-up visit, peripheral leukocytes in all 9 patients showed virtually complete depletion of GRODs and 7 of 9 patients manifested less irritability and/or improved alertness based upon parental and physician observations. Evaluation by Denver scale showed acquisition of no new developmental skills and retinal function assessed by ERG progressively declined. Most notably, average time to isoelectric EEG (indicating vegetative state) was significantly longer in our patients compared to that previously reported. MRI studies demonstrated signal abnormalities similar to previous reports. Brain volume and NAA declined steadily, but no published quantitative MRI or MRS studies of INCL patients are available for comparison on these measures. There were no adverse events related to therapy other than a mild gastrointestinal discomfort in 2 of 9 patients, which was eliminated when the liquid preparation of cysteamine bitatrate was replaced with capsules. Interpretation The objectively demonstrated benefits in our study are the depletion of GRODs and delay of isoelectric EEG in all patients; in addition, several subjective benefits were suggested, all of which warrant further study. Nevertheless, this report systematically and quantitatively documents the natural history of 9 INCL patients with the most lethal CLN1/PPT1 mutations and thereby provides a benchmark for evaluating future experimental therapies. Fu...

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Section: Discussionmentioning

confidence: 99%

Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study

Levin

Baker

Zein

et al. 2014

The Lancet Neurology

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“…However, to be clinically relevant, it is important to determine if the results derived from in vitro experiments are reproducible in vivo. Thus, we generated the Ppt1 -KI mice, which provide a platform for evaluating not only PTC124, but also other nonsense suppressors alone or in combination with a recently characterized thioesterase-mimetic small molecule, N-tert (Butyl) hydroxylamine (NtBuHA) 38. Moreover, our Ppt1 -KI mice may also be used as a platform for evaluating novel treatment strategies for INCL patients carrying nonsense mutations in the PPT1 gene including a combination of NtBuHA and nonsense suppressors 24.…”

Section: Discussionmentioning

confidence: 99%

Mice homozygous for c.451C>T mutation in Cln1 gene recapitulate INCL phenotype

Bouchelion

Zhang

et al. 2014

Ann Clin Transl Neurol

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ObjectiveNonsense mutations account for 5–70% of all genetic disorders. In the United States, nonsense mutations in the CLN1/PPT1 gene underlie >40% of the patients with infantile neuronal ceroid lipofuscinosis (INCL), a devastating neurodegenerative lysosomal storage disease. We sought to generate a reliable mouse model of INCL carrying the most common Ppt1 nonsense mutation (c.451C>T) found in the United States patient population to provide a platform for evaluating nonsense suppressors in vivo.MethodsWe knocked-in c.451C>T nonsense mutation in the Ppt1 gene in C57 embryonic stem (ES) cells using a targeting vector in which LoxP flanked the Neo cassette, which was removed from targeted ES cells by electroporating Cre. Two independently targeted ES clones were injected into blastocysts to generate syngenic C57 knock-in mice, obviating the necessity for extensive backcrossing.ResultsGeneration of Ppt1-KI mice was confirmed by DNA sequencing, which showed the presence of c.451C>T mutation in the Ppt1 gene. These mice are viable and fertile, although they developed spasticity (a “clasping” phenotype) at a median age of 6 months. Autofluorescent storage materials accumulated throughout the brain regions and in visceral organs. Electron microscopic analysis of the brain and the spleen showed granular osmiophilic deposits. Increased neuronal apoptosis was particularly evident in cerebral cortex and abnormal histopathological and electroretinographic (ERG) analyses attested striking retinal degeneration. Progressive deterioration of motor coordination and behavioral parameters continued until eventual death.InterpretationOur findings show that Ppt1-KI mice reliably recapitulate INCL phenotype providing a platform for testing the efficacy of existing and novel nonsense suppressors in vivo.

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“…Various experimental therapies have been tested to treat forebrain pathology in Ppt1 −/− mice, including antioxidants (19,20), enzyme replacement therapy (ERT) (21,22), human neuronal stem cells (23), and forebrain-directed gene therapy (12,(24)(25)(26)(27). Of these, adeno-associated virus (AAV) vector-mediated gene transfer has been the most promising (3,28).…”

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Synergistic effects of treating the spinal cord and brain in CLN1 disease

Shyng

Nelvagal

Dearborn

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

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Infantile neuronal ceroid lipofuscinosis (INCL, or CLN1 disease) is an inherited neurodegenerative storage disorder caused by a deficiency of the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). It was widely believed that the pathology associated with INCL was limited to the brain, but we have now found unexpectedly profound pathology in the human INCL spinal cord. Similar pathological changes also occur at every level of the spinal cord of PPT1-deficient (Ppt1 −/− ) mice before the onset of neuropathology in the brain. Various forebrain-directed gene therapy approaches have only had limited success in Ppt1 −/− mice. Targeting the spinal cord via intrathecal administration of an adeno-associated virus (AAV) gene transfer vector significantly prevented pathology and produced significant improvements in life span and motor function in Ppt1 −/− mice. Surprisingly, forebrain-directed gene therapy resulted in essentially no PPT1 activity in the spinal cord, and vice versa. This leads to a reciprocal pattern of histological correction in the respective tissues when comparing intracranial with intrathecal injections. However, the characteristic pathological features of INCL were almost completely absent in both the brain and spinal cord when intracranial and intrathecal injections of the same AAV vector were combined. Targeting both the brain and spinal cord also produced dramatic and synergistic improvements in motor function with an unprecedented increase in life span. These data show that spinal cord pathology significantly contributes to the clinical progression of INCL and can be effectively targeted therapeutically. This has important implications for the delivery of therapies in INCL, and potentially in other similar disorders.infantile Batten disease | adeno-associated virus | spinal cord | brain | combination therapy

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Neuroprotection and lifespan extension in Ppt1−/− mice by NtBuHA: therapeutic implications for INCL

Cited by 67 publications

References 49 publications

Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study

Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study

Mice homozygous for c.451C>T mutation in Cln1 gene recapitulate INCL phenotype

Synergistic effects of treating the spinal cord and brain in CLN1 disease

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