Experimental therapies in the neuronal ceroid lipofuscinoses

Neverman, Nicole J.; Best, Hannah; Hofmann, Sandra L.; Hughes, Stephanie M.

doi:10.1016/j.bbadis.2015.04.026

Cited by 30 publications

(28 citation statements)

References 95 publications

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“…Our results thus establish a framework to interpret the accumulation of SCMAS upon CLN6 and CLN8 deficiency as being caused by the depletion of the SCMAS degrading proteins, TPP1 and CTSD, at the lysosome. These observations also suggest therapeutic opportunities based on the possibility to provide the depleted enzymes exogenously via enzyme replacement therapy, an option that is being tested for several lysosomal enzymes including CLN2 but that is not available for transmembrane proteins such as CLN6 and CLN8 (62)(63)(64)(65).…”

Section: Discussionmentioning

confidence: 99%

A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer

Bajaj

Ronza

Zheng³

et al. 2019

Preprint

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Lysosomal enzymes are synthesized in the endoplasmic reticulum (ER) and transferred to the Golgi complex by interaction with the Batten disease protein CLN8. Here we investigated the relationship of this pathway with CLN6, an ER-associated protein of unknown function that is defective in a different Batten disease subtype. Experiments focused on protein interaction and trafficking identified CLN6 as an obligate component of a CLN6-CLN8 complex (herein referred to as EGRESS: ER-to-Golgi relaying of enzymes of the lysosomal system) which recruits lysosomal enzymes at the ER to promote their Golgi transfer. Simultaneous deficiency of CLN6 and CLN8 did not aggravate mouse pathology compared to the single deficiencies, indicating that the EGRESS complex works as a functional unit. Mutagenesis experiments showed that the second luminal loop of CLN6 is required for the interaction of CLN6 with the enzymes but dispensable for interaction with CLN8, and in vitro and in vivo studies showed that CLN6 deficiency results in inefficient ER export of lysosomal enzymes and diminished levels of the enzymes at the lysosome. These results identify CLN6 and the EGRESS complex as key players in lysosome biogenesis and shed light on the molecular etiology of Batten disease caused by defects in CLN6.

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Section: Discussionmentioning

confidence: 99%

A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer

Bajaj

Ronza

Zheng³

et al. 2019

Preprint

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“…1 Apart from a recently approved enzyme replacement therapy for the CLN2 disease (cerliponase alfa, BioMarin Pharmaceutical), there are no effective treatments, although several gene and enzyme replacement therapy trials are underway (NCT01161576, NCT01414985, NCT02485899, and NCT02725580; https:// clinicaltrials.gov) following studies in animal models. [2][3][4][5][6] Disease-relevant animal models are invaluable for the development and validation of therapies. However, encouraging preliminary data from gene therapy studies in murine forms 2,3,7,8 need careful consideration before proceeding to translation in human medicine because there are serious caveats with studies in mice.…”

Section: Introductionmentioning

confidence: 99%

Longitudinal In Vivo Monitoring of the CNS Demonstrates the Efficacy of Gene Therapy in a Sheep Model of CLN5 Batten Disease

et al. 2018

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Neuronal ceroid lipofuscinoses (NCLs; Batten disease) are neurodegenerative lysosomal storage diseases predominantly affecting children. Single administration of brain-directed lentiviral or recombinant single-stranded adeno-associated virus 9 (ssAAV9) vectors expressing ovine CLN5 into six pre-clinically affected sheep with a naturally occurring CLN5 NCL resulted in long-term disease attenuation. Treatment efficacy was demonstrated by non-invasive longitudinal in vivo monitoring developed to align with assessments used in human medicine. The treated sheep retained neurological and cognitive function, and one ssAAV9-treated animal has been retained and is now 57 months old, almost triple the lifespan of untreated CLN5-affected sheep. The onset of visual deficits was much delayed. Computed tomography and MRI showed that brain structures and volumes remained stable. Because gene therapy in humans is more likely to begin after clinical diagnosis, self-complementary AAV9-CLN5 was injected into the brain ventricles of four 7-month-old affected sheep already showing early clinical signs in a second trial. This also halted disease progression beyond their natural lifespan. These findings demonstrate the efficacy of CLN5 gene therapy, using three different vector platforms, in a large animal model and, thus, the prognosis for human translation.

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“…For the enzymatic deficiencies, enzyme replacement and gene therapy are promising approaches that are actively undergoing clinical development [4]. However, the unresolved functions for the other NCL proteins, which are less compatible with gene/protein replacement approaches, remains problematic for targeted therapy development.…”

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confidence: 99%

Genetics of the neuronal ceroid lipofuscinoses (Batten disease)

Mole

Cotman

2015

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

271

300

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The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders that affect children and adults, and are grouped together by similar clinical features and the accumulation of autofluorescent storage material. More than a dozen genes containing over 430 mutations underlying human NCLs have been identified. These genes encode lysosomal enzymes (CLN1, CLN2, CLN10, CLN13), a soluble lysosomal protein (CLN5), a protein in the secretory pathway (CLN11), two cytoplasmic proteins that also peripherally associate with membranes (CLN4, CLN14), and many transmembrane proteins with different subcellular locations (CLN3, CLN6, CLN7, CLN8, CLN12). For most NCLs, the function of the causative gene has not been fully defined. Most of the mutations in these genes are associated with a typical disease phenotype, but some result in variable disease onset, severity and progression, including distinct clinical phenotypes. There remain disease subgroups with unknown molecular genetic backgrounds. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.

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Experimental therapies in the neuronal ceroid lipofuscinoses

Cited by 30 publications

References 95 publications

A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer

A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer

Longitudinal In Vivo Monitoring of the CNS Demonstrates the Efficacy of Gene Therapy in a Sheep Model of CLN5 Batten Disease

Genetics of the neuronal ceroid lipofuscinoses (Batten disease)

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