scholarly journals Evaluation of mutant huntingtin and neurofilament proteins as potential markers in Huntington’s disease

2018 ◽  
Vol 10 (458) ◽  
pp. eaat7108 ◽  
Author(s):  
Lauren M. Byrne ◽  
Filipe B. Rodrigues ◽  
Eileanor B. Johnson ◽  
Peter A. Wijeratne ◽  
Enrico De Vita ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Mutant Huntingtin ◽  
Resonance Imaging ◽  
Neurofilament Light ◽  
Effective Strategies ◽  
Mutation Carriers ◽  
In Silico Modeling

Huntington’s disease (HD) is a genetic progressive neurodegenerative disorder, caused by a mutation in the HTT gene, for which there is currently no cure. The identification of sensitive indicators of disease progression and therapeutic outcome could help the development of effective strategies for treating HD. We assessed mutant huntingtin (mHTT) and neurofilament light (NfL) protein concentrations in cerebrospinal fluid (CSF) and blood in parallel with clinical evaluation and magnetic resonance imaging in premanifest and manifest HD mutation carriers. Among HD mutation carriers, NfL concentrations in plasma and CSF correlated with all nonbiofluid measures more closely than did CSF mHTT concentration. Longitudinal analysis over 4 to 8 weeks showed that CSF mHTT, CSF NfL, and plasma NfL concentrations were highly stable within individuals. In our cohort, concentration of CSF mHTT accurately distinguished between controls and HD mutation carriers, whereas NfL concentration, in both CSF and plasma, was able to segregate premanifest from manifest HD. In silico modeling indicated that mHTT and NfL concentrations in biofluids might be among the earliest detectable alterations in HD, and sample size prediction suggested that low participant numbers would be needed to incorporate these measures into clinical trials. These findings provide evidence that biofluid concentrations of mHTT and NfL have potential for early and sensitive detection of alterations in HD and could be integrated into both clinical trials and the clinic.

Neural Transplantation for Huntington's Disease: Experimental Rationale and Recommendations for Clinical Trials

1996 ◽  
Vol 5 (2) ◽  
pp. 339-352 ◽  
Author(s):  
Kathleen M. Shannon ◽  
Jeffrey H. Kordower
Keyword(s):  
Clinical Trials ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Treatment Strategies ◽  
Neural Transplantation ◽  
Trophic Factors ◽  
Trophic Factor ◽  
Striatal Neurons ◽  
Variable Parameters

Huntington's disease (HD) is a neurodegenerative disorder affecting motor function, personality, and cognition. This paper reviews the experimental data that demonstrate the potential for transplantation of fetal striatum and trophic factor secreting cells to serve as innovative treatment strategies for HD. Transplantation strategies have been effective in replacing lost neurons or preventing the degeneration of neurons destined to die in both rodent and nonhuman primate models of HD. In this regard, a logical series of investigations has proven that grafts of fetal striatum survive, reinnervate the host, and restore function impaired following excitotoxic lesions of the striatum. Furthermore, transplants of cells genetically modified to secrete trophic factors such as nerve growth factor protect striatal neurons from degeneration due to excitotoxicity or mitochondrial dysfunction. Given the disabling and progressive nature of HD, coupled with the absence of any meaningful medical therapy, it is reasonable to consider clinical trials of neural transplantation for this disease. Fetal striatal implants will most likely be the first transplant strategy attempted for HD. This paper describes the variable parameters we believe to be critical for consideration for the design of clinical trials using fetal striatal implants for the treatment of HD.

Huntington’s disease

2020 ◽  
pp. 83-92
Author(s):  
Juliana R Dutra ◽  
Tanya P Garcia ◽  
Karen Marder
Keyword(s):  
Clinical Trials ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Genetic Mutation ◽  
Current Standard ◽  
Disease Modifying ◽  
Disease Modifying Agents ◽  
A Current

Huntington’s disease (HD) is an autosomal dominant, neurodegenerative disorder caused by an unstable expansion in the cytosine adenine guanine (CAG) trinucleotide repeat in the huntingtin gene. The disease onsets gradually over many years and its symptoms include extrapyramidal movement disorder, cognitive impairment, and behavioural changes. Understanding the overall progression of HD is critical to designing clinical trials with possible disease modifying agents. Research in this area has exploded in the past two decades, as different multicentre studies have evaluated both clinical and biological measures in individuals at different stages of the disease (i.e. at-risk for the genetic mutation, pre-manifest, and manifest HD). In this chapter, we provide readers with a current understanding of HD progression. This includes an overview of the current standard for how HD is clinically evaluated, descriptive epidemiology of the disease, genetics of HD, and a review of potential disease modifiers.

D09 Parallel evaluation of mutant huntingtin and neurofilament light as biomarkers for huntington’s disease: the hd-csf study

2018 ◽  
Author(s):  
Lauren M Byrne ◽  
Filipe B Rodrigues ◽  
Eileanoir B Johnson ◽  
Peter A Wijeratne ◽  
Enrico De Vita ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mutant Huntingtin ◽  
Neurofilament Light ◽  
Parallel Evaluation

scholarly journals Latent Toxoplasma gondii infection increases soluble mutant huntingtin and promotes neurodegeneration in the YAC128 mouse model of Huntington’s disease

2019 ◽  
Author(s):  
David W. Donley ◽  
Teal Jenkins ◽  
Cailin Deiter ◽  
Reed Campbell ◽  
Marley Realing ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Latent Infection ◽  
Neurodegenerative Disorder ◽  
Cag Repeat ◽  
Mutant Huntingtin ◽  
Large Variability ◽  
Yac128 Mouse

AbstractToxoplasma gondii causes a prevalent neuroinvasive protozoal pathogen that in immune competent individuals results in latent infection characterized by intra-cellular parasite cysts in brain. Despite life-long infection, the role of latent toxoplasmosis on chronic neurodegenerative processes is poorly understood. Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a dominant CAG repeat expansion in the huntingtin gene (HTT) that results in the expression and accumulation of mutant huntingtin protein (mHTT). The mutant HD gene is fully penetrant. However, there is significant variability in disease progression that is in part explained by as yet unidentified environmental factors. The kynurenine pathway of tryptophan metabolism (KP) is an inflammatory pathway and its activation is implicated in HD pathogenesis. KP upregulation also occurs in response to infection with Toxoplasma gondii suggesting that the latent infection may promote HD. We discovered that mice on the FVB/NJ background develop latent toxoplasmosis following infection with the ME49 strain of T. gondii. This finding enabled us to address the hypothesis that latent toxoplasmosis potentiates disease in the YAC128 mouse model of HD, as these mice are maintained on the FVB/NJ background. Wild-type and HD mice were infected at 2-months of age. During the 10-month follow-up, infection had adverse effects on mice of both genotypes. However, YAC128 HD mice demonstrated specific vulnerability to latent toxoplasmosis, as demonstrated by the presence of increased striatal degeneration, high levels of the blood neurodegeneration marker neurofilament light protein, and elevated brain soluble mHTT. Our studies have uncovered a novel HD-infection interaction in mice that provides insights into the large variability of the human HD phenotype.

scholarly journals Huntington’s disease alters human neurodevelopment

Science ◽  
2020 ◽  
Vol 369 (6505) ◽  
pp. 787-793 ◽  
Author(s):  
Monia Barnat ◽  
Mariacristina Capizzi ◽  
Esther Aparicio ◽  
Susana Boluda ◽  
Doris Wennagel ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cell Polarity ◽  
Cell Cycle Progression ◽  
Neurodegenerative Disorder ◽  
Mouse Embryos ◽  
Junctional Complex ◽  
Mutant Huntingtin ◽  
Cycle Progression ◽  
Interkinetic Nuclear Migration

Although Huntington’s disease is a late-manifesting neurodegenerative disorder, both mouse studies and neuroimaging studies of presymptomatic mutation carriers suggest that Huntington’s disease might affect neurodevelopment. To determine whether this is actually the case, we examined tissue from human fetuses (13 weeks gestation) that carried the Huntington’s disease mutation. These tissues showed clear abnormalities in the developing cortex, including mislocalization of mutant huntingtin and junctional complex proteins, defects in neuroprogenitor cell polarity and differentiation, abnormal ciliogenesis, and changes in mitosis and cell cycle progression. We observed the same phenomena in Huntington’s disease mouse embryos, where we linked these abnormalities to defects in interkinetic nuclear migration of progenitor cells. Huntington’s disease thus has a neurodevelopmental component and is not solely a degenerative disease.

scholarly journals Mutant huntingtin and neurofilament light have distinct longitudinal dynamics in Huntington’s disease

2020 ◽  
Vol 12 (574) ◽  
pp. eabc2888
Author(s):  
Filipe B. Rodrigues ◽  
Lauren M. Byrne ◽  
Rosanna Tortelli ◽  
Eileanoir B. Johnson ◽  
Peter A. Wijeratne ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Prognostic Biomarker ◽  
Disease Status ◽  
Rate Of Change ◽  
Mutant Huntingtin ◽  
Clinical Progression ◽  
Neurofilament Light ◽  
Longitudinal Dynamics ◽  
Better Than

The longitudinal dynamics of the most promising biofluid biomarker candidates for Huntington’s disease (HD)—mutant huntingtin (mHTT) and neurofilament light (NfL)—are incompletely defined. Characterizing changes in these candidates during disease progression could increase our understanding of disease pathophysiology and help the identification of effective therapies. In an 80-participant cohort over 24 months, mHTT in cerebrospinal fluid (CSF), as well as NfL in CSF and blood, had distinct longitudinal trajectories in HD mutation carriers compared with controls. Baseline analyte values predicted clinical disease status, subsequent clinical progression, and brain atrophy, better than did the rate of change in analytes. Overall, NfL was a stronger monitoring and prognostic biomarker for HD than mHTT. Nonetheless, mHTT has prognostic value and might be a valuable pharmacodynamic marker for huntingtin-lowering trials.

scholarly journals Magnetic resonance imaging of Huntington's disease: preparing for clinical trials

Neuroscience ◽  
2009 ◽  
Vol 164 (1) ◽  
pp. 205-219 ◽  
Author(s):  
S. Klöppel ◽  
S.M. Henley ◽  
N.Z. Hobbs ◽  
R.C. Wolf ◽  
J. Kassubek ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Clinical Trials ◽  
Magnetic Resonance ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Resonance Imaging

scholarly journals Longitudinal dynamics of mutant huntingtin and neurofilament light in Huntington’s disease: the prospective HD-CSF study

2020 ◽  
Author(s):  
Filipe B. Rodrigues ◽  
Lauren M. Byrne ◽  
Rosanna Tortelli ◽  
Eileanoir B. Johnson ◽  
Peter A. Wijeratne ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Disease Status ◽  
Rate Of Change ◽  
Mutant Huntingtin ◽  
Neurofilament Light ◽  
Longitudinal Dynamics ◽  
Therapeutic Development ◽  
History Of ◽  
Better Than

AbstractThe longitudinal dynamics of the most promising biofluid biomarker candidates for Huntington’s disease (HD) – mutant huntingtin (mHTT) and neurofilament light (NfL) – are incompletely defined, but could help understand the natural history of the disease and how these biomarkers might help in therapeutic development and the clinic. In an 80-participant cohort over 24 months, mHTT in cerebrospinal fluid (CSF), and NfL in CSF and blood, had distinct longitudinal trajectories in HD mutation carriers compared with controls. Baseline analyte values predicted clinical disease status and subsequent clinical progression and brain atrophy, better than did the rate of change in analytes. Overall NfL was a stronger monitoring and prognostic biomarker for HD than mHTT. Nonetheless, mHTT possesses prognostic value and is a valuable pharmacodynamic marker for huntingtin-lowering trials.

Pharmaceutical, cellular and genetic therapies for Huntington's disease

2005 ◽  
Vol 110 (1) ◽  
pp. 73-88 ◽  
Author(s):  
Olivia J. Handley ◽  
Jenny J. Naji ◽  
Stephen B. Dunnett ◽  
Anne E. Rosser
Keyword(s):  
Clinical Trials ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Therapeutic Intervention ◽  
Neurodegenerative Disorder ◽  
Gene Encoding ◽  
Huntingtin Protein ◽  
Polyglutamine Expansion ◽  
Recent Advances

HD (Huntington's disease) is a devastating neurodegenerative disorder caused by a polyglutamine expansion in the gene encoding the huntingtin protein. Presently, there is no known cure for HD and existing symptomatic treatments are limited. However, recent advances have identified multiple pathological mechanisms involved in HD, some of which have now become the focus of therapeutic intervention. In this review, we consider progress made towards developing safe and effective pharmaceutical-, cell- and genetic-based therapies, and discuss the extent to which some of these therapies have been successfully translated into clinical trials. These new prospects offer hope for delaying and possibly halting this debilitating disease.

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