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Novel Approaches to Treating AL Amyloidosis using Innovative Models

Based on groundbreaking research using zebrafish models, Brigham and Women’s Hospital (BWH) investigators, led by Ronglih Liao, PhD, in collaboration with Calum A. MacRae, MD, PhD, Chief of Cardiovascular Medicine, and Rodney H. Falk, MD, Director of the BWH Cardiac Amyloidosis Program, are introducing novel approaches to address the underlying pathogenesis of AL amyloidosis.

“As there are no targeted therapies for amyloid cardiomyopathy, and prognosis for these patients remains poor, our goal is to bring new treatments to patients as quickly as possible through a strong translational research collaboration between basic science researchers and clinical experts,” said Dr. Liao.

Building a Foundation

Previously, the team discovered that human amyloidogenic light chain proteins resulted in cardiac dysfunction, cell death, and early mortality in zebrafish – establishing zebrafish as ideal models for research in AL amyloidosis. This work was published in the American Journal of Physiology - Heart and Circulatory Physiology (Am J Physiol Heart Circ Physiol. 2013 Jul 1;305(1):H95-103.) and has led to ongoing study of the mechanisms of disease and potential therapeutic targets using zebrafish. Previous findings by BWH researchers also have found that human AL light chain proteins bring about excessive reactive oxygen species (ROS) production and subsequent cellular dysfunction and cell death (Figure 1), but the cellular pathogenesis was unknown.

Uncovering Targeted Therapeutics

The team used human amyloidogenic light chains isolated from patients with amyloid cardiomyopathy to reveal that lysosomal dysregulation of autophagic flux is critical for mediating amyloidogenic light chain proteotoxicity (EMBO Mol Med. 2014 Nov; 6(11): 1493–1507.). Restoration of autophagic flux in cardiomyocytes exposed to AL-LC was achieved through the use of rapamycin, an mTOR inhibitor and potent enhancer of both autophagosome formation and clearance (Figures 2 and 3).

Along with decreased p62 levels, rapamycin-treated cardiomyocytes showed significant attenuation of both mitochondrial dysfunction and intracellular ROS levels and protection against AL-LC-induced cellular contractile dysfunction. These findings were present in both cellular and zebrafish models.

“Our work suggests that rapamycin may be a potential therapeutic approach for the treatment of AL amyloidosis,” said Dr. Falk. “This is exciting, as rapamycin is already FDA approved for other uses.”

  • Ronglih Liao, PhD
    Division of Genetics, Division of Cardiovascular Medicine
  • Calum A. MacRae, MD, PhD
    Chief, Cardiovascular Medicine
  • Rodney H. Falk, MD
    Director, Cardiac Amyloidosis Program

Cardiac Amyloidosis Program

The Brigham and Women’s Hospital (BWH) Cardiac Amyloidosis Program is one of few clinical programs in the United States that is focusing exclusively on cardiac amyloidosis. Led by Rodney H. Falk, MD, this program was established to address an unmet need in the diagnosis and treatment of systemic amyloidosis, with the goal of acquiring a better understanding of the disease and improving care for patients.

Advances in evaluation and treatment in the Cardiac Amyloidosis Program rely on a critical collaboration between clinicians and researchers at BWH. Recent highlights include:

  • Largest clinical study of patients with transthyretin-related amyloidosis, evaluating a new drug specifically designed to halt disease progression;
  • Establishment of the safety of endomyocardial biopsy for the diagnosis of cardiac amyloidosis and the effectiveness and outcome of treating atrial rhythm disturbances in amyloidosis;
  • Evaluation of new radiotracers to facilitate the earlier detection of systemic amyloidosis.

“Our team serves as a comprehensive resource for referring physicians and their patients with suspected or documented cardiac amyloidosis, providing them with access to the latest diagnostic techniques, clinical trials, and therapies,” said Dr. Falk.


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