Methods of treating neurological disorders
Inventors
Navia, Manuel A. • Roet, Kasper • Fleming, Jonathan
Assignees
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Publication Number
US-11752200-B2
Publication Date
2023-09-12
Expiration Date
Abstract
Disclosed is a method for treating a subject having a neurological disorder characterized by the presence of toxic proteins comprising contacting the cerebrospinal fluid (CSF) of the subject with an agent capable of removing or degrading the toxic protein.
Core Innovation
The invention relates to a CSF-treatment strategy for treating neurological disorders in a subject by contacting cerebrospinal fluid (CSF) containing toxic proteins with proteases. Contacting degrades and/or removes toxic proteins from the CSF, thereby treating the subject. The disclosed approach is directed to toxic proteins including TDP-43 and also describes tau, including hyperphosphorylated tau and tau aggregates, oligomers, dimers, and fragments.
The partial content further characterizes proteases by class, including serine, aspartic, cysteine, and metalloproteases, and identifies examples of proteases such as trypsin and elastase. It further describes trypsin or elastase immobilized on an agarose substrate as a defined contacting system, including use of a concentration gradient.
The partial content further describes patient selection and monitoring by detecting toxic proteins in CSF, including detection of TDP-43 and tau. It also provides device concepts for ex vivo or in situ contacting of CSF, including contacting CSF in situ in a subject. Experimental examples in the partial content show protease activity with immobilized agarose systems and digestion of TDP-43 and tau-related species, together with reduced toxicity of protease-treated tau.
Claims Coverage
The partial content provides two independent claims, each directed to treating ALS or FTD by contacting patient CSF with a specific immobilized protease on agarose in the form of a concentration gradient, where CSF contains TDP-43 and contacting removes TDP-43. Across both independent claims, the inventive features focus on the specific protease, immobilization on an agarose substrate, and concentration-gradient immobilization to remove TDP-43 from CSF, thereby treating ALS or FTD.
Immobilized trypsin on agarose concentration-gradient for removing TDP-43 from CSF
Contacting the CSF of the subject with trypsin immobilized on an agarose substrate at a concentration of 1-10 milligrams per milliliter, wherein the CSF comprises TDP-43, and contacting removes TDP-43 from the CSF, thereby treating the subject, wherein trypsin is immobilized on an agarose substrate in the form of a concentration gradient of 1-10 milligrams per milliliter of trypsin.
Immobilized elastase on agarose concentration-gradient for removing TDP-43 from CSF
Contacting the CSF of the subject with elastase immobilized on an agarose substrate at a concentration of 1-10 milligrams per milliliter, wherein the CSF comprises TDP-43, and contacting removes TDP-43 from the CSF, thereby treating the subject, wherein elastase is immobilized on an agarose substrate in the form of a concentration gradient of 1-10 milligrams per milliliter of elastase.
Both independent claims cover treating ALS or FTD by contacting a subject’s CSF containing TDP-43 with a protease (trypsin or elastase) immobilized on an agarose substrate, where the immobilized protease is present as a concentration gradient, and the contacting removes TDP-43 from CSF to treat the subject.
Stated Advantages
Contacting removes TDP-43 from CSF, thereby treating the subject.
Documented Applications
Treating amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) in a subject by contacting the subject’s CSF containing TDP-43 with immobilized trypsin or elastase on an agarose substrate.
Diagnosing and/or monitoring patient suitability by detecting TDP-43 in CSF before contacting.
Contacting CSF in situ in a subject for the treatment workflow.
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