Compositions and methods for predicting age of onset of a lysosomal storage disease or a disease associated with a lysosomal defect
Inventors
Pavan, William J. • Rodriguez, Jorge L. • Larson, Denise M. • Porter, III, Forbes D.
Assignees
US Department of Health and Human Services
Publication Number
US-9983200-B2
Publication Date
2018-05-29
Expiration Date
2034-03-14
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The present invention features diagnostic compositions and methods for predicting the age of onset of a lysosomal storage disease or a disease associated with a lysosomal defect in subject.
Core Innovation
The invention features diagnostic compositions and methods for predicting the age of onset of a lysosomal storage disease or a disease associated with a lysosomal defect in a subject. It specifically provides methods that involve detecting fluorescence in a cell sample of the subject before and after contacting the cells with a detectable probe that accumulates in acidic cellular compartments, and calculating the fold-change in fluorescence. This fold-change is then compared to a reference, wherein the magnitude of the fold-change in fluorescence is indicative of the age of disease onset.
The invention addresses the problem that in certain lysosomal storage diseases, such as Niemann-Pick disease type C1 (NPC1), accurate prognostic information is difficult because the disease is extremely heterogeneous in clinical presentation, mutation spectrum, and lacks concordance between predicted consequences of NPC1 gene mutation and clinical timing or severity. Current diagnostic methods provide limited ability to predict the age of disease onset, which impacts patient management and treatment. The invention provides a novel assay correlating lysosomal fluorescence changes in patient-derived cells with the age of disease onset, thus overcoming current diagnostic limitations.
In particular, the invention details that in subjects with lysosomal storage diseases or diseases associated with lysosomal defects, the greater the fold-change in lysosomal fluorescence, the younger the age of disease onset, and conversely, smaller fold-changes correspond to older age of onset. For example, a fold-change in fluorescence greater than 15 indicates a younger onset (e.g., neonate to 2 years), while smaller fold-changes indicate later onset (e.g., over 6 years). The methods enable predicting age of onset by measuring lysosomal fluorescence fold-changes in cells such as epithelial cells, fibroblasts, or white blood cells obtained from biopsy or blood samples.
Claims Coverage
The patent includes two independent claims focused on methods involving the detection and quantification of fold-change in lysosomal fluorescence to predict Niemann-Pick disease onset and to diagnose and treat the disease.
Method of diagnosing and treating Niemann-Pick disease using fold-change fluorescence
A method comprising obtaining a cell sample, detecting fluorescence before and after contacting cells with an acidic-compartment-accumulating detectable probe, calculating fold-change in fluorescence compared to a reference wherein fold-change ranges of 20-35 and 5-15 predict early infantile and later onset respectively, and administering a therapeutically effective amount of cyclodextrin to the diagnosed subject.
Method of detecting fold-change fluorescence in a subject's cell sample
A method that involves obtaining a cell sample from a subject, detecting fluorescence before and after contacting cells with a detectable probe accumulating in acidic cellular compartments, calculating fold-change in fluorescence and comparing it to a reference, wherein the fold-change is in specific ranges (5-15 or 20-35) indicative of disease onset categories.
The claims cover methods that use detecting and quantifying fluorescence fold-changes in cells stained with lysosome-accumulating probes to predict disease onset of Niemann-Pick disease and to guide treatment with agents such as cyclodextrin. The claims also include related detection methods defining fold-change ranges associated with different onset categories, with specified detection techniques and sample types.
Stated Advantages
Provides accurate prediction of age of onset for lysosomal storage diseases, such as Niemann-Pick disease, allowing improved patient management.
The assay is simple, inexpensive, and non-invasive, usable with various cell types obtained from biopsy or blood samples.
Allows monitoring of treatment efficacy by measuring fold-change in fluorescence periodically during therapy.
Enables identification of agents useful in treating lysosomal storage diseases by screening for reduction in fold-change fluorescence.
Provides critical prognostic information for diseases with heterogeneous clinical presentations and genetic mutations.
Documented Applications
Predicting the age of onset of lysosomal storage diseases including Batten (CLN2), Fabry, Farber, Niemann-Pick disease types A and C1, Sanfilippo type B (MPS IIIB), Tay-Sachs disease, and diseases associated with lysosomal defects such as Parkinson's and Alzheimer's diseases.
Monitoring disease state or treatment efficacy in subjects with Niemann-Pick disease by measuring fold-change in lysosomal fluorescence in patient-derived cells.
Screening and identifying therapeutic agents that reduce lysosomal storage defects as indicated by decreased fold-change in fluorescence, including agents like cyclodextrin and tocopherol.
Treatment selection and adjustment based on predicted age of disease onset derived from measured fold-change in fluorescence.
Interested in licensing this patent?