Substrate Reduction Therapy in Four Patients with Milder CLN1 Mutations and Juvenile-Onset Batten Disease Using Cysteamine Bitartrate

Gavin, Maureen; Wen, Guang Y.; Messing, Jeffrey M.; Adelman, Scott; Logush, A.; Jenkins, EdmundC.; Brown, W. Ted; Velinov, Milen

doi:10.1007/8904_2013_226

Cited by 24 publications

(12 citation statements)

References 12 publications

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“…This is promising as it indicates that some clinical benefit can be gained through phosphocysteamine therapy, at least in the area of quality of life. Consistent with the pre-clinical data obtained in the murine model of infantile CLN1 disease, the results of a recent clinical trial in children with INCL showed that systemic treatment with phosphocysteamine provided little clinical benefit (Gavin et al 2013). However, it remains possible that the addition of this treatment to more complex combination therapy approaches (eg.…”

Section: Introductionsupporting

confidence: 62%

Pathogenesis and therapies for infantile neuronal ceroid lipofuscinosis (infantile CLN1 disease)

Hawkins-Salsbury

Cooper

Sands

2013

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The Neuronal Ceroid Lipofuscinoses (NCL, Batten Disease) are a group of inherited neurodegenerative diseases. Infantile Neuronal Ceroid lipofuscinosis (INCL, Infantile Batten Disease, or infantile CLN1 disease) is caused by a deficiency in the soluble lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1) and has the earliest onset and fastest progression of all the NCLs. Several therapeutic strategies including enzyme replacement, gene therapy, stem cell-mediated therapy, and small molecule drugs have resulted in minimal to modest improvements in the murine model of PPT1-deficiency. However, more recent studies using various combinations of these approaches have shown more promising results; in some instances more than doubling the life span of PPT1-deficient mice. These combination therapies that target different pathogenic mechanisms may offer the hope of treating this profoundly neurodegenerative disorder. Similar approaches may be useful when treating other forms of NCL caused by deficiencies in soluble lysosomal proteins. Different therapeutic targets will need to be identified and novel strategies developed in order to effectively treat forms of NCL caused by deficiencies in integral membrane proteins such as Juvenile Neuronal Ceroid Lipofuscinosis. Finally, the challenge with all of the NCLs will lie in early diagnosis, improving the efficacy of the treatments, and effectively translating them into the clinic.

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Section: Introductionsupporting

confidence: 62%

Pathogenesis and therapies for infantile neuronal ceroid lipofuscinosis (infantile CLN1 disease)

Hawkins-Salsbury

Cooper

Sands

2013

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…We also searched using the terms “Infantile neuronal ceroid lipofuscinosis” AND “Cystagon” AND “clinical trial”. However, when we used the terms “infantile neuronal ceroid lipofuscinosis” AND “Cysteamine bitartrate” only one clinical study 45 was listed in which 4 patients with juvenile-onset INCL patients with mild PPT1 genotypes who were above 3 years of age were given only cysteamine bitartrate at a dose of 50mg/kg body weight. In that study, the age of the patients was higher and the dose of cysteamine bitartrate was lower than those used in our study.…”

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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“…Approaches to treating CLN1 include substrate reduction therapies, enzyme or gene-replacement therapies, and pharmacological intervention focused on mimicking PPT1 activity. Substrate reduction therapy trials have shown limited success (Gavin et al, 2013; Levin et al, 2014). In preclinical models, PPT1 mimetic treatment partially reverses disease phenotype and extends the lifespan of PPT1-null animals (Sarkar et al, 2013).…”

Section: Therapeutics For Cln1mentioning

confidence: 99%

Depalmitoylation by Palmitoyl-Protein Thioesterase 1 in Neuronal Health and Degeneration

Koster

Yoshii

2019

Front. Synaptic Neurosci.

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Protein palmitoylation is the post-translational, reversible addition of a 16-carbon fatty acid, palmitate, to proteins. Protein palmitoylation has recently garnered much attention, as it robustly modifies the localization and function of canonical signaling molecules and receptors. Protein depalmitoylation, on the other hand, is the process by which palmitic acid is removed from modified proteins and contributes, therefore, comparably to palmitoylated-protein dynamics. Palmitoylated proteins also require depalmitoylation prior to lysosomal degradation, demonstrating the significance of this process in protein sorting and turnover. Palmitoylation and depalmitoylation serve as particularly crucial regulators of protein function in neurons, where a specialized molecular architecture and cholesterol-rich membrane microdomains contribute to synaptic transmission. Three classes of depalmitoylating enzymes are currently recognized, the acyl protein thioesterases, α/β hydrolase domain-containing 17 proteins (ABHD17s), and the palmitoyl-protein thioesterases (PPTs). However, a clear picture of depalmitoylation has not yet emerged, in part because the enzyme-substrate relationships and specific functions of depalmitoylation are only beginning to be uncovered. Further, despite the finding that loss-of-function mutations affecting palmitoyl-protein thioesterase 1 (PPT1) function cause a severe pediatric neurodegenerative disease, the role of PPT1 as a depalmitoylase has attracted relatively little attention. Understanding the role of depalmitoylation by PPT1 in neuronal function is a fertile area for ongoing basic science and translational research that may have broader therapeutic implications for neurodegeneration. Here, we will briefly introduce the rapidly growing field surrounding protein palmitoylation and depalmitoylation, then will focus on the role of PPT1 in development, health, and neurological disease.

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Substrate Reduction Therapy in Four Patients with Milder CLN1 Mutations and Juvenile-Onset Batten Disease Using Cysteamine Bitartrate

Cited by 24 publications

References 12 publications

Pathogenesis and therapies for infantile neuronal ceroid lipofuscinosis (infantile CLN1 disease)

Pathogenesis and therapies for infantile neuronal ceroid lipofuscinosis (infantile CLN1 disease)

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

Depalmitoylation by Palmitoyl-Protein Thioesterase 1 in Neuronal Health and Degeneration

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