Progress in the Development of Small Molecule Therapeutics for the Treatment of Neuronal Ceroid Lipofuscinoses (NCLs)

Kinarivala, Nihar; Trippier, Paul C.

doi:10.1021/acs.jmedchem.5b01020

Cited by 17 publications

(15 citation statements)

References 104 publications

(290 reference statements)

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“…Intrathecal TPP1 is effective in slowing disease in CLN2 disease, but is expensive and medical coverage available only in few countries. Gene and/or protein replacement are not options for NCLs due to defective membrane proteins (CLN3/CLN6/CLN8), hence the need for alternate novel therapies accessible to all . Flupirtine is neuroprotective in human postmitotic neurons and photoreceptors .…”

Section: Discussionmentioning

confidence: 99%

Flupirtine derivatives as potential treatment for the neuronal ceroid lipofuscinoses

Makoukji

Saadeh

Mansour

et al. 2018

Ann Clin Transl Neurol

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ObjectiveNeuronal Ceroid Lipofuscinoses (NCL) are fatal inherited neurodegenerative diseases with established neuronal cell death and increased ceramide levels in brain, hence, a need for disease‐modifying drug candidates, with potential to enhance growth, reduce apoptosis and lower ceramide in neuronal precursor PC12 cells and human NCL cell lines using enhanced flupirtine aromatic carbamate derivatives in vitro.MethodsAromatic carbamate derivatives were tested by establishing growth curves under pro‐apoptotic conditions and activity evaluated by trypan blue and JC‐1 staining, as well as a drop in pro‐apoptotic ceramide in neuronal precursor PC12 cells following siRNA knockdown of the CLN3 gene, and CLN1‐/CLN2‐/CLN3‐/CLN6‐/CLN8 patient‐derived lymphoblasts. Ceramide levels were determined in CLN1‐/CLN2‐/CLN3‐/CLN6‐/CLN8 patient‐derived lymphoblasts before and after treatment. Expression of BCL‐2, ceramide synthesis enzymes (CERS2/CERS6/SMPD1/DEGS2) and Caspases 3/8/9 levels were compared in treated versus untreated CLN3‐deficient PC12 cells by qRT‐PCR.ResultsRetigabine, the benzyl‐derivatized carbamate and an allyl carbamate derivative were neuroprotective in CLN3‐defective PC12 cells and rescued CLN1‐/CLN2‐/CLN3‐/CLN6‐/CLN8 patient‐derived lymphoblasts from diminished growth and accelerated apoptosis. All drugs decreased ceramide in CLN1‐/CLN2‐/CLN3‐/CLN6‐/CLN8 patient‐derived lymphoblasts. Increased BCL‐2 and decreased ceramide synthesis enzyme expression were established in CLN3‐derived PC12 cells treated with the benzyl and allyl carbamate derivatives. They down‐regulated Caspase 3/Caspase 8 expression. Caspase 9 expression was reduced by the benzyl‐derivatized carbamate.InterpretationThese findings establish that compounds analogous to flupirtine demonstrate anti‐apoptotic activity with potential for treatment of NCL disease and use of ceramide as a marker for these diseases.

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Section: Discussionmentioning

confidence: 99%

Flupirtine derivatives as potential treatment for the neuronal ceroid lipofuscinoses

Makoukji

Saadeh

Mansour

et al. 2018

Ann Clin Transl Neurol

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“…5,6 These features are evident in the most prevalent neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), and Batten disease, the most common (yet rare) neurodegenerative disease of childhood. 1,5,7,8 Current treatment options for all of these disorders are symptomatic and do not slow or reverse disease progression. Pathophysiological similarities at the molecular level suggest that lessons learned from one neurodegenerative disease may be applicable to other diseases, leading to the design of pharmacological interventions with broad utility.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Aromatic Carbamates that Confer Neuroprotective Activity by Enhancing Autophagy and Inducing the Anti-Apoptotic Protein B-Cell Lymphoma 2 (Bcl-2)

et al. 2017

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Neurodegenerative diseases share certain pathophysiological hallmarks that represent common targets for drug discovery. In particular, dysfunction of proteostasis and the resultant apoptotic death of neurons represent common pathways for pharmacological intervention. A library of aromatic carbamate derivatives based on the clinically available drug flupirtine was synthesized to determine a structure–activity relationship for neuroprotective activity. Several derivatives were identified that possess greater protective effect in human induced pluripotent stem cell-derived neurons, protecting up to 80% of neurons against etoposide-induced apoptosis at concentrations as low as 100 nM. The developed aromatic carbamates possess physicochemical properties desirable for CNS therapeutics. The primary known mechanisms of action of the parent scaffold are not responsible for the observed neuroprotective activity. Herein, we demonstrate that neuroprotective aromatic carbamates function to increase the Bcl-2/Bax ratio to an antiapoptotic state and activate autophagy through induction of beclin 1.

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“…Accumulation of lipofuscin has been shown to result in autophagy dysfunction and lower turnover of affected mitochondria. This in turn creates a 16 feedback loop wherein defective mitochondria produce more reactive oxygen species (ROS; which is observed in our developed model system) that increase lipofuscin accumulation, questioning if activation of autophagy would necessarily clear lipofuscin accumulation (66). If the hydrolytic function of the lysosome is irreparably damaged by CLN3 mutation or other pathogenesis event, small molecule autophagy inducers would not be able to induce clearance.…”

Section: Discussionmentioning

confidence: 96%

“…Accumulation of subunit C of mitochondrial ATP synthase in lysosome-derived organelles is a hallmark of the NCLs; however, the exact biochemical mechanism of accumulation is unknown (8)(9)(10)(11). No cure for the NCLs has yet been realized (12)(13)(14)(15)(16). However there is one pharmacological intervention available; in 2017 the FDA approved the gene therapy Cerliponase® (Brineura) for CLN2 disease which is an enzyme replacement therapy for tripeptidyl peptidase 1 (TPP1) that can slow or halt progression of the disease (17).…”

Section: Introductionmentioning

confidence: 99%

Small Molecules that Rescue Multiple Phenotypic Aberrations in an iPSC-Derived Neuron Model of CLN3 Disease

Kinarivala¹,

Morsy²,

Carmona³

et al. 2020

Preprint

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<div> <div> <div> <p>The neuronal ceroid lipofuscinoses (NCLs) commonly referred to as Batten disease are a family of rare lysosomal storage disorders (LSDs). The most common form of NCL occurs in children harboring a mutation in the CLN3 gene. This form is lethal with no existing cure or treatment beyond symptomatic relief. The pathophysiology of CLN3 disease is complex and poorly understood, with the current in vivo and in vitro models failing to identify pharmacological targets for therapeutic intervention. This study reports the characterization of the first CLN3 patient-specific induced pluripotent stem cell (iPSC)-derived model of the blood-brain barrier (BBB) and adds to the few available iPSC-derived neuron models of the disease. Upon differentiation, hallmarks of CLN3 disease were displayed including lipofuscin and subunit C of mitochondrial ATP synthase accumulation, mitochondrial dysfunction and aberrant lysosomal pH. Small molecules were identified that cleared subunit C accumulation by the mTOR-independent modulation of autophagy, conferred protective effects through induction of Bcl-2 and rescued mitochondrial dysfunction. </p> </div> </div> </div>

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Progress in the Development of Small Molecule Therapeutics for the Treatment of Neuronal Ceroid Lipofuscinoses (NCLs)

Cited by 17 publications

References 104 publications

Flupirtine derivatives as potential treatment for the neuronal ceroid lipofuscinoses

Flupirtine derivatives as potential treatment for the neuronal ceroid lipofuscinoses

Discovery of Aromatic Carbamates that Confer Neuroprotective Activity by Enhancing Autophagy and Inducing the Anti-Apoptotic Protein B-Cell Lymphoma 2 (Bcl-2)

Small Molecules that Rescue Multiple Phenotypic Aberrations in an iPSC-Derived Neuron Model of CLN3 Disease

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