Monitoring of Early Disease Progression in Hereditary Transthyretin Amyloidosis

Study Overview
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Brief Summary
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This study measures circulating, misfolded ATTR oligomers in asymptomatic ATTRm amyloidosis genetic carriers longitudinally over five years.

Detailed Description
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Recent advances in genetic testing have allowed for pathogenic mutation identification in family members of affected individuals prior to onset of symptoms. While the presence of mutation and the corresponding TTR kinetic stability have been directly linked to disease development, the molecular drivers of tissue specific degeneration have not been defined. We hypothesize that soluble misfolded TTR oligomer species may be circulating within the blood of these patients possibly years prior to amyloid deposition and could serve as an early biomarker and/or driver for disease development. In this line, The Scripps Research Institute has developed a peptide-based probe that specifically labels and integrates into misfolded TTR oligomers allowing the relative circulating concentration in the bloodstream to be determined. Longitudinal monitoring of untreated, asymptomatic TTR amyloid genetic carriers utilizing the Scripps probe is likely to provide novel insight into early disease progression. We also plan to utilize the Scripps probe to monitor disease progression in TTR amyloid genetic carriers currently undergoing treatment by observing how treatments affect the circulating misfolded TTR oligomers. Through enhanced understanding of early disease progression and treatment efficacy, our hope is to limit amyloid accumulation in cardiac and nerve tissue and delay the development of the invariably fatal TTR amyloid cardiomyopathy/neuropathy.

Official Title
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Monitoring of Early Disease Progression in Hereditary Transthyretin Amyloidosis

Conditions
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Amyloidosis, Amyloid, Amyloid Neuropathies, Familial, Amyloid Cardiomyopathy, Amyloid - Primary, Transthyretin Amyloidosis, AL Amyloidosis

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with known hereditary ATTR amyloidosis genetic mutations as identified by genetic testing. Exclusion Criteria: Patients with ATTR amyloidosis identified as wild-type.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Primary<br>1.) To evaluate the relative amount of misfolded ATTR oligomers in asymptomatic ATTR amyloid genetic carriers and correlate their levels with clinical symptoms and outcomes. Determine if misfolded ATTR oligomers are elevated compared to healthy control data obtained by Scripps during probe development Describe the levels longitudinally Determine if treatment with ATTR-specific medications (examples: diflunisal, doxycycline, ursodiol, tauroursodeoxycholic acid (TUDCA), green tea extract, curcumin, tafamidis, inotersen, patisiran) lead to reduction in the probe levels in those with elevated levels at baseline | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average % change in oligomers in patients with new onset TTR amyloid symptoms | Change (%) for oligomer level at the time of TTR amyloid symptoms compared to baseline | Annually over 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| % change of oligomer levels relative to baseline level in patients with ATTR specific medication changes | Change (%) for oligomer level at the time of ATTR specific medication changes compared to baseline | Annually over 5 years |