AAV gene transfer delays disease onset in a TPP1-deficient canine model of the late infantile form of Batten disease

Katz, Martin L.; Tecedor, Luis; Chen, Yonghong; Williamson, Baye G.; Лысенко, Елена; Wininger, Fred A.; Young, W. E.; Johnson, Gayle C.; Whiting, Rebecca E.H.; Coates, Joan R.; Davidson, Beverly L.

doi:10.1126/scitranslmed.aac6191

Cited by 123 publications

(109 citation statements)

References 35 publications

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“…However, some of these enzymes – including NAGLU – are not able to cross the blood-brain barrier [13], which precludes systemic administration of the deficient enzyme as a direct route of enzyme supply. To overcome this hurdle, direct injection of corrective viruses to the cerebrospinal fluid and viral intraparenchymal injections are being investigated [67–69]. The promising preclinical results from this approach have led to it being tested in humans (a current example is described at ClinicalTrial.gov under ID No.…”

Section: Discussionmentioning

confidence: 99%

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

et al. 2018

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The accumulation of undegraded molecular material leads to progressive neurodegeneration in a number of lysosomal storage disorders (LSDs) that are caused by functional deficiencies of lysosomal hydrolases. To determine whether inducing macroautophagy/autophagy via small-molecule therapy would be effective for neuropathic LSDs due to enzyme deficiency, we treated a mouse model of mucopolysaccharidosis IIIB (MPS IIIB), a storage disorder caused by deficiency of the enzyme NAGLU (alpha-N-acetylglucosaminidase [Sanfilippo disease IIIB]), with the autophagy-inducing compound trehalose. Treated naglu–/ – mice lived longer, displayed less hyperactivity and anxiety, retained their vision (and retinal photoreceptors), and showed reduced inflammation in the brain and retina. Treated mice also showed improved clearance of autophagic vacuoles in neuronal and glial cells, accompanied by activation of the TFEB transcriptional network that controls lysosomal biogenesis and autophagic flux. Therefore, small-molecule-induced autophagy enhancement can improve the neurological symptoms associated with a lysosomal enzyme deficiency and could provide a viable therapeutic approach to neuropathic LSDs.Abbreviations: ANOVA: analysis of variance; Atg7: autophagy related 7; AV: autophagic vacuoles; CD68: cd68 antigen; ERG: electroretinogram; ERT: enzyme replacement therapy; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFAP: glial fibrillary acidic protein; GNAT2: guanine nucleotide binding protein, alpha transducing 2; HSCT: hematopoietic stem cell transplantation; INL: inner nuclear layer; LC3: microtubule-associated protein 1 light chain 3 alpha; MPS: mucopolysaccharidoses; NAGLU: alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB); ONL: outer nuclear layer; PBS: phosphate-buffered saline; PRKCA/PKCα: protein kinase C, alpha; S1BF: somatosensory cortex; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB; VMP/VPL: ventral posterior nuclei of the thalamus

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Section: Discussionmentioning

confidence: 99%

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

et al. 2018

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“…To date, systematic therapeutic interventions for canine NCLs have only been evaluated for the CLN8 disease in English Setters(Siakotos et al, 2001) and for the CLN2 disease in Miniature Longhaired Dachshunds (Katz et al, 2014; Katz et al, 2017; Katz et al, 2015; Tracy et al, 2016a; Vuillemenot et al, 2011; Vuillemenot et al, 2015; Whiting et al, 2016; Whiting et al, 2014). It has been reported that a major component of the storage material that accumulates in a number of the NCLs is subunit c protein, a subunit of mitochondrial ATP synthase (Palmer et al, 2013; Palmer et al, 1989) It was discovered that both the form of the subunit c protein stored in some of the NCLs and the form present in mitochondria from normal animals contains a trimethylated lysine (TML) residue (Katz et al, 1994b; Katz et al, 1995b; Katz and Gerhardt, 1992; Katz and Rodrigues, 1991; Katz et al, 1997).…”

Section: Investigation Of Therapeutic Interventions For Treating Tmentioning

confidence: 99%

“…An AAV2.TPP1 gene therapy vector was injected into the CSF of the lateral ventricles of the brain of affected dogs early in the disease. This treatment resulted in long-term high levels of TPP1 gene expression by the cells lining the ventricles and widespread distribution of functional TPP1 throughout the central nervous system (CNS) (Katz et al, 2015). The therapeutic efficacy of this treatment was similar to that obtained with the periodic infusions of recombinant TPP1.…”

Section: Investigation Of Therapeutic Interventions For Treating Tmentioning

confidence: 99%

Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions

Katz

Rustad²,

Robinson

et al. 2017

Neurobiology of Disease

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The neuronal ceroid lipofuscinoses (NCLs) are devastating inherited progressive neurodegenerative diseases, with most forms having a childhood onset of clinical signs. The NCLs are characterized by progressive cognitive and motor decline, vision loss, seizures, respiratory and swallowing impairment, and ultimately premature death. Different forms of NCL result from mutations in at least 13 genes. The clinical signs of some forms overlap significantly, so genetic testing is the only way to definitively determine which form an individual patient suffers from. At present, an effective treatment is available for only one form of NCL. Evidence of NCL has been documented in over 20 canine breeds and in mixed-breed dogs. To date, 12 mutations in 8 different genes orthologous to the human NCL genes have been found to underlie NCL in a variety of dog breeds. A Dachshund model with a null mutation in one of these genes is being utilized to investigate potential therapeutic interventions, including enzyme replacement and gene therapies. Demonstration of the efficacy of enzyme replacement therapy in this model led to successful completion of human clinical trials of this treatment. Further research into the other canine NCLs, with in-depth characterization and understanding of the disease processes, will likely lead to the development of successful therapeutic interventions for additional forms of NCL, for both human patients and animals with these disorders.

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“…Of these, adeno-associated virus (AAV) vector-mediated gene transfer has been the most promising (3,28). However, these therapies have met with only limited success, especially compared with efforts in CLN2 disease, another form of NCL caused by a lysosomal enzyme deficiency (29,30).…”

mentioning

confidence: 99%

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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AAV gene transfer delays disease onset in a TPP1-deficient canine model of the late infantile form of Batten disease

Cited by 123 publications

References 35 publications

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions

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

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