# Novel Therapeutic Strategies in the Understanding of Systemic Amyloid Disease

> **NIH NIH F31** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $22,320

## Abstract

PROJECT SUMMARY
Familial transthyretin amyloidosis (ATTR) is a devastating multi-systemic protein folding disorder that results
from over 100 possible mutations in the transthyretin (TTR) gene. In the disease, TTR misfolds, is secreted from
the liver, and aggregates extracellularly in a concentration-dependent manner at downstream target organs such
as the heart and/or peripheral nervous system. ATTR exhibits extreme mutation-dependent variation in disease
phenotype (e.g. target organ affected and severity) with an average time of diagnosis to death of only 5-10 years.
The current standards of care for patients with ATTR, including liver transplantation and small molecule TTR
stabilizers, are highly limited; not all patients are candidates for surgery, large donor organ deficits exist, and
many patients are refractory to kinetic stabilizers. A better understanding of disease etiology as well as alternative
treatment options are necessary to combat systemic amyloid disorders.
 Problematically, the multi-tissue nature of the disease makes it difficult to study in vitro, while no current
animal model accurately recapitulates ATTR pathology. To combat these limitations, our laboratory has
developed a novel, induced pluripotent stem cell (iPSC)-based model for studying ATTR. In our platform, patient-
derived iPSCs are differentiated into effector cells (hepatocyte-like cells) that produce mutant TTR. Conditioned
media is then prepared on these cells to (1) analyze the type and quantity of TTR species secreted and (2) dose
target cells (iPSC-derived cardiomyocytes and neurons) to assay resulting toxicity and the efficacy of proposed
therapeutics.
 Using our genetically tractable model, we look to improve the current therapeutic paradigm for ATTR.
Importantly, studies show that reducing serum levels of destabilized TTR through liver transplantation or
activation of stress-responsive protein folding machinery reduces target organ toxicity. Armed with this insight
and our iPSC-based ATTR model, we will test the hypothesis that disruption of aberrant TTR expression or
activation of endogenous protein folding machinery will prove therapeutic for ATTR. We propose to evaluate this
hypothesis through two Aims. In the first, to overcome limitations of site-specific gene editing approaches for
treating ATTR, we will develop a universal gene correction strategy ameliorative of all TTR genetic lesions. In
the second, we will activate the ATF6 pathway of the unfolded protein response (UPR) using genomic and
pharmacological approaches to selectively decrease production of destabilized, toxic TTR. In both methods,
secretion of TTR species and their impact on patient-matched iPSC-derived target cell (neuron and
cardiomyocyte) toxicity will be evaluated.
 Our iPSC-based model, described herein, allows for the unprecedented coupling of protein biochemistry
and genomic-based approaches to study novel aspects of systemic amyloidoses. Insight gained here will allow
for bet...

## Key facts

- **NIH application ID:** 9899736
- **Project number:** 5F31DK121481-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Richard Giadone
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $22,320
- **Award type:** 5
- **Project period:** 2019-04-01 → 2020-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899736

## Citation

> US National Institutes of Health, RePORTER application 9899736, Novel Therapeutic Strategies in the Understanding of Systemic Amyloid Disease (5F31DK121481-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9899736. Licensed CC0.

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