<i>MCOLN1</i>gene-replacement therapy corrects neurologic dysfunction in the mouse model of mucolipidosis IV

DeRosa, Samantha; Salani, Monica; Smith, Sierra; Sangster, Madison; Miller-Browne, Victoria; Wassmer, Sarah; Xiao, Ran; Vandenberghe, Luk; Slaugenhaupt, Susan A.; Misko, Albert L.; Grishchuk, Yulia

doi:10.1101/2020.12.06.413740

Cited by 4 publications

(2 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Loss of Mcoln1 expression in mice mimics human MLIV and results in motor and cognitive deficits, accompanied by the characteristic brain pathology hallmarks such as hypoplastic corpus callosum, hypomyelination, glia activation and lysosomal storage inclusions (18)(19)(20)(21). Motor deficits in mice become evident at 2 months of age and progress to hind-limb paralysis and premature death at around 7-8 months of age (21,22). Histological assessment of the end-stage brain pathology showed partial loss of cerebellar Purkinje cells, with otherwise largely preserved neuronal populations (19,20).…”

Section: Introductionmentioning

confidence: 99%

“…At present, clinical intervention for MLIV is limited to palliative care and management of some of the symptoms; however, CNS-targeted AAV-mediated gene transfer of MCOLN1 was recently shown to restore or prevent motor decline in Mcoln1 -/mice and ameliorate brain pathology (22). These preclinical data provide a new hope for developing disease-altering therapies for MLIV.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Plasma Proteomic Signature of Mucolipidosis Type IV

Tobin,

Misko,

Miller-Browne

et al. 2024

Preprint

View full text Add to dashboard Cite

Mucolipidosis IV (MLIV) is an autosomal-recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by the loss of function of the lysosomal channel transient receptor potential mucolipin-1, TRPML1, and is associated with an early brain phenotype consisting of glial reactivity, hypomyelination, lysosomal abnormalities, and increased cytokine expression. Although the field is approaching the first translationally relevant therapy, we currently lack a molecular signature of disease that can be used to detect therapeutic efficacy. In the current study, we analyzed 7,322 proteins in the plasma proteome and compare protein profiles with clinical measures of disease severity (motor function, muscle tone, and age). To do so, we used aptamer-based protein profiling on plasma isolated from 18 MLIV patients and 37 aged-matched controls from a biorepository. We identified a total of 1,961 differentially expressed proteins between MLIV and control subjects, with functions spanning many major hallmarks of MLIV. Our analysis revealed a decrease in the abundance of neuronal proteins and an increase in muscle proteins, consistent with the neuronal dysfunction and muscle pathology observed in patients. In particular, lower levels of synaptic proteins (e.g., GABARAP) best correlated with disease severity. Next, we compared the plasma proteome of patients to the brain proteome from the mouse model of MLIV and identified shared alterations in 45 proteins. The up-regulated overlapping proteins were largely related to lysosomal function (e.g., ACTN2, GLB1), while the down-regulated proteins were largely related to myelination (e.g. TPPP3, CNTN2). Both signatures are consistent with our understanding of key disease hallmarks: impaired myelination and modified lysosomal function. Collectively, these data indicate that peripheral blood plasma protein signatures mirror changes found in the MLIV brain and suggest candidate markers relevant to MLIV pathology to be validated in future studies.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Plasma Proteomic Signature of Mucolipidosis Type IV

Tobin,

Misko,

Miller-Browne

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Brain cell type specific proteomics approach to discover pathological mechanisms in the childhood CNS disorder mucolipidosis type IV

Sangster

Shahriar²,

Niziolek

et al. 2023

Preprint

View full text Add to dashboard Cite

1 Mucolipidosis IV (MLIV) is an ultra-rare, recessively inherited lysosomal disorder resulting from inactivating mutations in MCOLN1, the gene encoding the lysosomal cation channel TRPML1. The disease primarily affects the central nervous system (CNS) and manifests in the first year with cognitive and motor developmental delay, followed by a gradual decline in neurological function across the second decade of life, blindness, and premature death in third or fourth decades. Brain pathology manifestations in MLIV are consistent with hypomyelinating leukodystrophy with brain iron accumulation. Presently, there are no approved or investigational therapies for MLIV, and pathogenic mechanisms remain largely unknown. The MLIV mouse model, Mcoln1-/- mice, recapitulates all major manifestations of the human disease. Here, to better understand the pathological mechanisms in the MLIV brain, we performed cell type specific LC-MS/MS proteomics analysis in the MLIV mouse model and reconstituted molecular signatures of the disease in either freshly isolated populations of neurons, astrocytes, oligodendrocytes, and neural stem cells, or whole tissue cortical homogenates from young adult symptomatic Mcoln1-/- mice. Our analysis confirmed on the molecular level major histopathological hallmarks of MLIV universally present in Mcoln1-/- tissue and brain cells, such as hypomyelination, lysosomal dysregulation, and impaired metabolism of lipids and polysaccharides. Importantly, pathway analysis in brain cells revealed mitochondria-related alterations in all Mcoln1-/- brain cells, except oligodendrocytes, that was not possible to resolve in whole tissue. We also report unique proteome signatures and dysregulated pathways for each brain cell population used in this study. These data shed new light on cell-intrinsic mechanisms of MLIV and provide new insights for biomarker discovery and validation to advance translational studies for this disease.

show abstract

A blood-brain-barrier penetrant AAV gene therapy rescues neurological deficits in mucolipidosis IV mice

Sangster,

Bishop,

Yao

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Mucolipidosis IV (MLIV) is a rare, autosomal recessive, lysosomal disease characterized by intellectual disability, motor deficits and progressive vision loss. Using AAV9 and AAV-PHP.B as delivery vectors, we previously demonstrated the feasibility of modifying disease course in a mouse model of MLIV by the humanMCOLN1gene transfer. Here, using a primate-enabling capsid AAV.CPP.16 (CPP16), we constructed a new, clinic-orientedMCOLN1gene expression vector and demonstrated its efficacy in the preclinical model of MLIV. Systemic administration of CPP16-MCOLN1in adult symptomaticMcoln1-/-mice at a dose of 1e12 vg per mouse resulted inMCOLN1expression in the brain and peripheral tissues, alleviated brain pathology, rescued neuromotor function, and completely prevented paralysis. Notable expression ofMCOLN1transcripts was also detected in the retina of the mouse that had exhibited significant degeneration at the time of the treatment. However, no increase of retinal thickness was observed after the gene therapy treatment. Our results suggest a new AAV-based systemic gene replacement therapy for the treatment of MLIV that could be translated into clinical studies.

show abstract

MCOLN1gene-replacement therapy corrects neurologic dysfunction in the mouse model of mucolipidosis IV

Cited by 4 publications

References 50 publications

Plasma Proteomic Signature of Mucolipidosis Type IV

Plasma Proteomic Signature of Mucolipidosis Type IV

Brain cell type specific proteomics approach to discover pathological mechanisms in the childhood CNS disorder mucolipidosis type IV

A blood-brain-barrier penetrant AAV gene therapy rescues neurological deficits in mucolipidosis IV mice

Contact Info

Product

Resources

About