Method for diagnosing a neurodegenerative disease
Inventors
Pickering-Brown, Stuart • Traynor, Bryan • Singleton, Andrew B. • Morris, Huw • Heutink, Peter • Hardy, John • Tienari, Pentti
Assignees
HOSPITAL DISTRICT OF HELSINKI AND UUSIMAA • University College Cardiff Consultants Ltd • University of Manchester • UCL Business Ltd • VU UNIVERSITY MEDICAL CENTRE AMSTERDAM • Vu University Medical Centre Armsterdam • National Institute on Aging • US Department of Health and Human Services
Publication Number
US-9896729-B2
Publication Date
2018-02-20
Expiration Date
2032-08-31
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Abstract
The present invention relates to methods of assessing whether a subject has or is likely to develop a neurodegenerative disease comprising determining whether the subject has a mutation in the C9orf72 gene wherein said mutation prevents or disrupts C9orf72 expression relative to expression in a reference from subjects without the mutation.
Core Innovation
The invention provides methods of assessing whether a subject has or is likely to develop a neurodegenerative disease by determining whether the subject has a mutation in the C9orf72 gene wherein said mutation prevents or disrupts C9orf72 expression relative to expression in a reference from subjects without the mutation. The methods include detecting insertions, deletions, or expansions, particularly hexanucleotide (GGCCCC or GGGGCC) repeat expansions in intron 1 of the C9orf72 gene, which lead to reduced or abolished C9orf72 expression or the expression of non-functional protein.
The problem addressed is the lack of sensitive and reliable diagnostic and prognostic tests for neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). Existing diagnostic methods based on neuropsychological tests, brain imaging, and physical symptoms may fail to detect patients early or those with increased risk, thereby missing opportunities for early therapeutic intervention. The invention addresses the need for molecular tests that can identify mutations in the C9orf72 gene associated with neurodegenerative disorders, enabling earlier diagnosis and assessment of predisposition.
The invention further provides isolated nucleic acid molecules comprising intron 1 of the C9orf72 gene containing hexanucleotide repeat expansions, methods of analyzing protein levels or activity of C9orf72 to identify subjects predisposed to or suffering from neurodegenerative disease, genetically modified non-human animals bearing mutations in the C9orf72 gene for use as disease models, therapeutic agents comprising C9orf72 protein or nucleic acids encoding same for preventing or treating neurodegenerative diseases, and screening methods to identify compounds that increase C9orf72 protein amount or function.
Claims Coverage
The patent includes multiple claims focusing on detecting hexanucleotide repeats in the C9orf72 gene for diagnosing neurodegenerative diseases, as well as methods using nucleic acid probes and hybridization techniques. The following independent inventive features are extracted from those claims.
Method of detecting hexanucleotide repeat expansion in C9orf72 gene or mRNA
A method comprising obtaining a sample from a subject, mixing the sample with a labeled nucleic acid oligonucleotide comprising a GGCCCC or GGGGCC hexanucleotide repeat, and detecting hybridization to the repeat starting at position 27,573,527 on chromosome 9 (forward strand), thereby identifying the hexanucleotide expansion associated with disease.
Method of diagnosing a subject as having or at increased risk of FTLD or MND/ALS based on hexanucleotide repeat expansion
A method comprising obtaining a sample, mixing it with a labeled nucleic acid oligonucleotide comprising GGCCCC repeats, detecting hybridization to the hexanucleotide repeat starting at position 27,573,527 on chromosome 9, where increased binding indicates the presence of at least 30 repeats, and diagnosing the subject as having or at increased risk of FTLD, MND/ALS, or combination thereof. Variations include subjects having at least 100, 500, 600, 700, or 1,000 repeats.
The independent claims focus on nucleic acid-based methods for detecting the hexanucleotide repeat expansion in the C9orf72 gene, particularly at position 27,573,527, to diagnose or assess risk for FTLD and MND/ALS. The methods employ labeled oligonucleotides and various hybridization and amplification detection techniques such as PCR, qPCR, southern blotting, and conformational analyses.
Stated Advantages
Enables early and sensitive detection of subjects predisposed to or suffering from neurodegenerative diseases such as FTLD and MND/ALS, improving diagnostic accuracy over prior neuropsychological and imaging tests.
Facilitates prognosis and presymptomatic screening allowing clinicians to initiate preventative or therapeutic measures before debilitating symptoms manifest.
Provides a robust molecular marker (hexanucleotide repeat expansion in C9orf72) that accounts for a major genetic cause of familial and sporadic ALS and FTLD, particularly in European populations.
Offers utility in developing animal models and screening assays for therapeutic agents targeting C9orf72-associated neurodegeneration.
Documented Applications
Assessing whether a subject has or is likely to develop frontotemporal lobar degeneration (FTLD) or motor neuron disease (MND)/amyotrophic lateral sclerosis (ALS) by detecting mutations or expansions in C9orf72 gene.
Diagnostic and prognostic testing of nucleic acid samples from humans, particularly genomic DNA or mRNA, using techniques such as repeat-primed PCR and Southern blotting.
Measuring and comparing C9orf72 protein levels or activity in bodily samples, including blood-derived plasma or serum, for diagnosing or monitoring neurodegenerative disease progression.
Generating non-human genetically modified animals with C9orf72 mutations as models for neurodegenerative disease research and compound screening.
Administering C9orf72 protein, nucleic acids encoding C9orf72, or agents that mimic or promote C9orf72 activity as therapeutic treatments to prevent or treat neurodegenerative disorders.
Administering agents such as antisense oligonucleotides or siRNA molecules targeting mutant C9orf72 mRNA to prevent or treat mRNA toxicity and neurodegeneration.
Screening compounds for ability to increase amount or function of C9orf72 protein as candidate treatments for neurodegenerative diseases.
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