KR-20260066110-A - Methods for diagnosing amyloid disease

Abstract

The present disclosure relates, in some aspects, to a method and composition for detecting amyloid-related diseases in an individual.

Inventors

• 월, 조나단 에스.
• 마틴-슐러, 에밀리 브룩

Assignees

• 유니버시티 오브 테네시 리서치 파운데이션

Dates

Publication Date

20260512

Application Date

20240906

Priority Date

20230907

Claims (20)

1. As a method for diagnosing early-stage amyloid-related disease in individuals at risk of developing amyloid-related disease, a. A step of administering to an individual an amyloid-reactive peptide comprising an amino acid sequence presented in any one of sequence identification numbers 1-14 conjugated to a detectable label; and b. A step of detecting the amount of amyloid-reactive peptide by detecting the amount of detectable marker in the tissue or organ of an individual. A method comprising, wherein an amount of amyloid-reactive peptide exceeding a threshold indicates that the individual has an amyloid-related disease, where the amyloid-related disease is an early-stage amyloid-related disease.
2. The method of claim 1, wherein the individual is determined to be at risk of amyloid-related disease based on the presence of a gene mutation, having multiple myeloma, having amyloid-positive laminectomy tissue, having amyloid-positive tissue from carpal tunnel release, having monoclonal gammaglobulinopathy of unknown significance (MGUS), having heart failure with preserved ejection fraction (HFpEF), having heart failure with reduced ejection fraction (HFrEF), belonging to a susceptible ethnic group, or being elderly.
3. In paragraph 2, a method in which the gene mutation is present within the transthyretin protein.
4. In paragraph 2, the method in which the gene mutation is present in the fibrinogen α protein.
5. A method in which, in any one of paragraphs 1 to 3, the individual does not have symptoms of amyloidosis.
6. A method according to any one of claims 1 to 3, wherein the individual has neuropathic symptoms of amyloid disease.
7. A method according to any one of claims 1 to 6, wherein the individual was previously diagnosed as not having an amyloid-related disease.
8. As a method for diagnosing early-stage amyloid-related disease in individuals suspected of having amyloid-related disease, a. A step of administering to an individual an amyloid-reactive peptide comprising an amino acid sequence presented in any one of sequence identification numbers 1-14 conjugated to a detectable label; and b. A step of detecting the amount of amyloid-reactive peptide by detecting the amount of detectable marker in the tissue or organ of an individual. A method comprising, wherein an amount of amyloid-reactive peptide exceeding a threshold indicates that the individual has an amyloid-related disease, where the amyloid-related disease is an early-stage amyloid-related disease.
9. As a method for determining the prognosis of individuals with amyloid-related diseases, a. A step of administering an amyloid-reactive peptide comprising an amino acid sequence presented in any one of sequence identification numbers 1-14 conjugated to a detectable label to an individual, and detecting the amount of the amyloid-reactive peptide by detecting the amount of the detectable label in the tissue or organ of the individual to quantify amyloid in the individual for the first time; b. A step of administering an amyloid-reactive peptide comprising an amino acid sequence presented in any one of sequence identification numbers 1-14 conjugated to a detectable label to an individual, and a step of quantifying amyloid in the individual a second time by detecting the amount of the detectable label in the tissue or organ of the individual; and c. A step of determining the individual's prognosis by comparing the first quantified amyloid in the tissue or organ with the second quantified amyloid in the tissue or organ. A method including
10. A method according to claim 8, wherein the prognosis of an individual having an amyloid-related disease is based on detecting the amount of amyloid-reactive peptide in the heart alone.
11. A method according to claim 8, wherein the prognosis of an individual having an amyloid-related disease is based on detecting the amount of amyloid-reactive peptides in the heart and kidneys.
12. A method according to claim 8, wherein the prognosis of an individual having amyloid-related disease is based on detecting the amount of amyloid-reactive peptides in the heart, kidneys, and all other organs.
13. As a method for treating amyloid-related diseases, a. A step of administering to an individual an amyloid-reactive peptide comprising an amino acid sequence presented in any one of sequence identification numbers 1-14 conjugated to a detectable label; b. A step of detecting the amount of amyloid-reactive peptide by detecting the amount of detectable label in the tissue or organ of an individual; and c. Step of administering treatment for amyloid-related diseases when the amount of amyloid-reactive peptides exceeds a threshold. A method including
14. In paragraph 13, the method in which the individual has an early stage amyloid-related disease.
15. As a method for monitoring the treatment of amyloid-related diseases in individuals, a. A step of administering an amyloid-reactive peptide comprising an amino acid sequence presented in any one of sequence identification numbers 1-14 conjugated to a detectable label to an individual, and detecting the amount of the amyloid-reactive peptide by detecting the amount of the detectable label in the tissue or organ of the individual to quantify amyloid in the individual for the first time; b. Step of administering treatment for amyloid-related diseases; c. A step of administering an amyloid-reactive peptide comprising an amino acid sequence presented in any one of sequence identification numbers 1-14 conjugated to a detectable label to an individual, and a step of quantifying amyloid in the individual a second time by detecting the amount of the detectable label in the tissue or organ of the individual; and d. A step of determining whether the treatment is effective by comparing the first quantified amyloid in the tissue or organ with the second quantified amyloid in the tissue or organ. A method including
16. A method according to any one of claims 1 to 15, further comprising the step of administering an amyloid-reactive peptide comprising an amino acid sequence presented in any one of sequence identification numbers 1-14 conjugated to a detectable label to an individual, and detecting the amount of the amyloid-reactive peptide by detecting the amount of the detectable label in the tissue or organ of the individual to quantify amyloid in the individual a second, optionally a third, a fourth, and/or a fifth time.
17. A method in which the first and second are separated by at least 6 weeks in paragraph 15 or 16.
18. As a method for selecting treatment for amyloid-related diseases in individuals, a. A step of administering to an individual an amyloid-reactive peptide comprising an amino acid sequence presented in any one of sequence identification numbers 1-14 conjugated to a detectable label; and b. A step of detecting the amount of amyloid-reactive peptide by detecting the amount of detectable marker in the tissue or organ of an individual. A method comprising, wherein if amyloid is detected in the heart, treatment for amyloid-related disease is administered, and if amyloid is not detected in the heart, alternative therapy is administered.
19. As a method of managing treatment for amyloid-related diseases in individuals, a. A step of administering an amyloid-reactive peptide comprising an amino acid sequence presented in any one of sequence identification numbers 1-14 conjugated to a detectable label to an individual, and detecting the amount of the amyloid-reactive peptide by detecting the amount of the detectable label in the tissue or organ of the individual to quantify amyloid in the individual for the first time; b. Step of administering treatment for amyloid-related diseases; c. A step of administering an amyloid-reactive peptide comprising an amino acid sequence presented in any one of sequence identification numbers 1-14 conjugated to a detectable label to an individual, and detecting the amount of the detectable label in the tissue or organ of the individual to quantify amyloid in the individual a second time; d. A step of comparing the first quantified amyloid in a tissue or organ with the second quantified amyloid in a tissue or organ; and e. Steps for coordinating treatment for amyloid-related diseases A method including
20. In paragraph 19, a method in which treatment is changed when the amyloid disease is stable between the first and second.

Description

Methods for diagnosing amyloid disease Cross-reference regarding related applications The present application claims priority to U.S. provisional application No. 63/581,213 filed September 7, 2023 and U.S. provisional application No. 63/657,715 filed June 7, 2024, the full text of which is incorporated herein by reference. Reference to the electronic sequence list The contents of the electronic sequence list (165992001240SEQLIST.xml; size: 40,979 bytes; and creation date: September 6, 2024) are incorporated herein by reference in their entirety. field The present disclosure relates to a method for diagnosing amyloid-related diseases in some aspects. Systemic amyloidosis is a progressive protein misfolding disorder characterized by the extracellular deposition of proteinaceous fibrils, extracellular matrix components, and serum proteins. In particular, the accumulation of amyloid within the heart and kidneys, the organs most affected in all types of amyloidosis, leads to organ dysfunction, poor quality of life, and ultimately death. Although approximately 20 different proteins have been identified as fibrillary components in systemic amyloidosis (Aimo A, Merlo M, Porcari A, et al. Eur J Heart Fail. 2022); patients with variant or wild-type transthyretin- (ATTRv and ATTRwt), immunoglobulin light chain- (AL), and leukocyte chemotactic factor 2- (ALECT2) associated amyloidosis account for more than 90% of cases diagnosed in the United States (Edwards CV, Rao N, Bhutani D, et al. Blood. 2021;138:2632-2641). Cardiac amyloidosis is an ominous sign in both AL and ATTR-associated amyloidosis, causing restrictive hypertrophic cardiomyopathy, particularly of the left ventricular wall and interventricular septum, accompanied by abnormalities in electrical conduction and strain (Garcia-Pavia P, Aus Dem Siepen F, Donal E, et al. N Engl J Med. 2023:NEJMoa2303765). However, any organ or tissue may be affected, leading to a heterogeneous clinical presentation and making accurate and rapid diagnosis difficult (Dorbala S, Cuddy S, Falk RH. JACC Cardiovasc Imaging. 2020;13:1368-1383). Non-invasive imaging is particularly useful for diagnostic algorithms for cardiac amyloidosis (Dorbala S, Park MA, Cuddy S, et al. J Nucl Med. 2021;62:716-722). While echocardiography and cardiac magnetic resonance imaging (CMR) can reveal structural abnormalities and functional sequelae associated with amyloidosis,10 these techniques are not amyloid-specific. Nuclear imaging using 99m Tc-pyrophosphate ( 99m Tc-PyP) or 99m Tc-3,3-diphosphono-1,2-propanedicarboxylic acid (DPD) is commercially used to diagnose cardiac ATTR amyloidosis. These bone-searching agents bind to cardiac microcalcifications associated with cardiac amyloid and preferentially detect only ATTR-associated cardiac amyloidosis (Antoni G, Lubberink M, Estrada S, et al. J Nucl Med. 2013;54:213-220). In some respects, existing methods are limited by the unavailability of amyloid-specific measures for monitoring changes in amyloid load over time. Therefore, non-invasive and quantitative measures for detecting and monitoring extracardiac as well as cardiac amyloid deposits would be clinically beneficial. Methods and compositions addressing these and other needs are provided herein. In one aspect, a method for diagnosing an early-stage amyloid-related disease in an individual at risk of developing an amyloid-related disease comprises: a) administering to the individual an amyloid-reactive peptide comprising an amino acid sequence presented in any one of SEQ ID NO: 1-14 conjugated to a detectable label; and b) detecting an amount of the amyloid-reactive peptide by detecting an amount of the detectable label in a tissue or organ of the individual, wherein an amount of the amyloid-reactive peptide exceeding a threshold indicates that the individual has an amyloid-related disease, wherein the amyloid-related disease is an early-stage amyloid-related disease. In some embodiments, an individual is determined to be at risk of amyloid-related disease based on the presence of a gene mutation, having multiple myeloma, having amyloid-positive laminectomy tissue, having amyloid-positive tissue from carpal tunnel release, having monoclonal gammaglobulinopathy of unknown significance (MGUS), having heart failure with preserved ejection fraction (HFpEF), having heart failure with reduced ejection fraction (HFrEF), belonging to a susceptible ethnic group, or being elderly. In some embodiments, the gene mutation is in the transthyretin protein. In some embodiments, the gene mutation is in the fibrinogen α protein. In some embodiments, the individual does not have symptoms of amyloidosis. In some embodiments, the individual has neuropathic symptoms of amyloid disease. In some embodiments, the individual was previously diagnosed as not having amyloid-related disease. In another aspect, a method for diagnosing an early-stage amyloid-related disease in an individual suspected of having an amyloid-related d