Imaging gene delivery in a mouse model of congenital neuronal ceroid lipofuscinosis

Pike, Lisa; Tannous, Bakhos A.; Deliolanis, Nikolaos C.; Hsich, Gary; Morse, Danielle; Tung, Ching–Hsuan; Sena‐Esteves, Miguel; Breakefield, Xandra O.

doi:10.1038/gt.2011.118

Cited by 16 publications

(4 citation statements)

References 53 publications

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“…Quality of life improved profoundly, with only 2 of 12 treated animals having progressed to the most debilitating symptoms such as dysequilibrium and severe ataxia. Clinical outcomes were similar for the 2 vector serotypes tested: AAV1, currently in human clinical trials (36–39) or approved for human use (40, 41), and AAVrh8, a new serotype (42) that showed promise in a related feline model (28). …”

Section: Discussionmentioning

confidence: 93%

Sustained Normalization of Neurological Disease after Intracranial Gene Therapy in a Feline Model

et al. 2014

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Progressive debilitating neurological defects characterize feline GM1 gangliosidosis, a lysosomal storage disease caused by deficiency of lysosomal β-galactosidase. No effective therapy exists for affected children, who often die before age 5. In the current study, an adeno-associated viral vector carrying the therapeutic gene was injected bilaterally into two brain targets (thalamus and deep cerebellar nuclei) of a feline model of GM1 gangliosidosis. Gene therapy normalized β-galactosidase activity and storage throughout the brain and spinal cord. The mean survival of 12 treated GM1 animals was >38 months compared to 8 months for untreated animals. Seven of the 8 treated animals remaining alive demonstrated normalization of disease, with abrogation of many symptoms including gait deficits and postural imbalance. Sustained correction of the GM1 gangliosidosis disease phenotype after limited intracranial targeting by gene therapy in a large animal model suggests that this approach may be useful for treating the human version of this lysosomal storage disorder.

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Section: Discussionmentioning

confidence: 93%

Sustained Normalization of Neurological Disease after Intracranial Gene Therapy in a Feline Model

et al. 2014

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“…The rapidly expanding body of research into normal glial biology and their responses to disease has facilitated a reassessment that glia are not just passive bystanders of pathology in the CNS, but instead are active determinants of neurodegeneration. As summarized in this review, there is substantial evidence suggesting such glial involvement in NCL pathophysiology, and changes in glial activation are frequently used to evaluate therapeutic efficacy in preclinical studies ( 4 , 11 , 15 , 23 , 26 , 34 , 43 – 47 , 97 ). Of necessity, this review focusses primarily upon the three most common forms of NCL, CLN1 disease, CLN2 disease and CLN3 disease, in which the issue of glial contribution to pathogenesis has been considered.…”

Section: Discussionmentioning

confidence: 99%

“…This approach theoretically has the advantage that a single one-time administration of viral vector should restore deficient lysosomal proteins to transduced cells ( 41 , 42 ). Preclinical studies of gene therapy in animal models of CLN1, CLN2, CLN3, CLN6, CLN7, and CLN10 diseases have shown promising results ( 4 , 23 , 34 , 43 – 47 ). However, clinical studies in children with CLN2 disease treated with gene therapy showed considerably less efficacy ( 48 , 49 ), highlighting the difficulty of translating advances from mice directly into human patients ( 50 ).…”

Section: Introductionmentioning

confidence: 99%

Glial Dysfunction and Its Contribution to the Pathogenesis of the Neuronal Ceroid Lipofuscinoses

et al. 2022

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While significant efforts have been made in developing pre-clinical treatments for the neuronal ceroid lipofuscinoses (NCLs), many challenges still remain to bring children with NCLs a cure. Devising effective therapeutic strategies for the NCLs will require a better understanding of pathophysiology, but little is known about the mechanisms by which loss of lysosomal proteins causes such devastating neurodegeneration. Research into glial cells including astrocytes, microglia, and oligodendrocytes have revealed many of their critical functions in brain homeostasis and potential contributions to neurodegenerative diseases. Genetically modified mouse models have served as a useful platform to define the disease progression in the central nervous system across NCL subtypes, revealing a wide range of glial responses to disease. The emerging evidence of glial dysfunction questions the traditional “neuron-centric” view of NCLs, and would suggest that directly targeting glia in addition to neurons could lead to better therapeutic outcomes. This review summarizes the most up-to-date understanding of glial pathologies and their contribution to the pathogenesis of NCLs, and highlights some of the associated challenges that require further research.

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“…Of note, the significant attenuation of disease progression has also been observed in a recent clinical trial on CLN2 patients treated biweekly with intracerebroventricular injections of recombinant TPP1 [ 103 ]. Remarkable therapeutic outcomes have also been achieved in the Ctsd ko mouse, despite the rapid disease progression using an adeno-associated virus (AAV) vector-mediated gene transfer to the brain and/or the viscera [ 52 , 104 ]. Furthermore, we recently showed that injections of recombinant human pro-CTSD (rhCTSD) resulted in the partial correction of various pathological markers in the brain, the attenuation of the visceral pathology and a prolonged life span of treated mice [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Rapid and Progressive Loss of Multiple Retinal Cell Types in Cathepsin D-Deficient Mice—An Animal Model of CLN10 Disease

Bassal

Liu

Jankowiak

et al. 2021

Cells

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Vision loss is among the characteristic symptoms of neuronal ceroid lipofuscinosis (NCL), a fatal neurodegenerative lysosomal storage disorder. Here, we performed an in-depth analysis of retinal degeneration at the molecular and cellular levels in mice lacking the lysosomal aspartyl protease cathepsin D, an animal model of congenital CLN10 disease. We observed an early-onset accumulation of storage material as indicated by elevated levels of saposin D and subunit C of the mitochondrial ATP synthase. The accumulation of storage material was accompanied by reactive astrogliosis and microgliosis, elevated expression of the autophagy marker sequestosome 1/p62 and a dysregulated expression of several lysosomal proteins. The number of cone photoreceptor cells was reduced as early as at postnatal day 5. At the end stage of the disease, the outer nuclear layer was almost atrophied, and all cones were lost. A significant loss of rod and cone bipolar cells, amacrine cells and ganglion cells was found at advanced stages of the disease. Results demonstrate that cathepsin D deficiency results in an early-onset and rapidly progressing retinal dystrophy that involves all retinal cell types. Data of the present study will serve as a reference for studies aimed at developing treatments for retinal degeneration in CLN10 disease.

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Imaging gene delivery in a mouse model of congenital neuronal ceroid lipofuscinosis

Cited by 16 publications

References 53 publications

Sustained Normalization of Neurological Disease after Intracranial Gene Therapy in a Feline Model

Sustained Normalization of Neurological Disease after Intracranial Gene Therapy in a Feline Model

Glial Dysfunction and Its Contribution to the Pathogenesis of the Neuronal Ceroid Lipofuscinoses

Rapid and Progressive Loss of Multiple Retinal Cell Types in Cathepsin D-Deficient Mice—An Animal Model of CLN10 Disease

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