Treating ATTR Amyloidosis Now a Possibility as Novel Immunotherapy Enters Clinical Trial

Our researchers at the Chakrabartty lab have identified a novel immunotherapeutic drug target in the transthyretin (TTR) protein. This is a common transport protein that carries thyroxine through the blood and cerebrospinal fluid. If monomeric TTR is ever found misfolded it will not form its native homo-tetramer correctly (originally in the blood this protein native structure is comprised of four identical smaller subunits). These misfolded TTR ‘building blocks’ will naturally clump together and form larger sticky and disordered oligomeric structures and fibers that can deposit in tissues around the body. For misfolded TTR, these misfolded fibrous plaques are usually deposited in the heart and if not cleared in time cause a condition known as amyloid-TTR amyloidosis (ATTR amyloidosis).

 

Transthyretin (TTR) Misfolding Pathway

Figure 1. Here is the pathological kinetic pathway for TTR amyloidosis. ATTR Amyloidosis is a heart disease caused by the aggregation of misfolded monomeric subunits of the tetrameric transthyretin (TTR) protein into fibrous amyloid filaments that are deposited in the ventricles of the heart.

 

Because of the poor diagnostics and lack of treatment, ATTR amyloidosis is currently an endemic in Sweden, Portugal and Japan. In the USA, 3-4% of African Americans are predisposed to this disease (via the I122L mutation). The most common genetic form of ATTR amyloidosis worldwide is caused by a single point mutation V30M [1,2]. Due to the invasive and impractical nature of current diagnostic biopsy’s, many patients with the disease are not diagnosed until after death [3]. There is an ever pressing need for new life saving diagnostics and treatments to be developed for ATTR Amyloidosis.

Treating amyloid-Transthyretin (ATTR) amyloidosis

 

Our lab has successfully engineered immunological therapeutic antibodies that were able to detect low concentrations the bad misfolded forms of TTR in blood plasma samples, while leaving the normal and native forms undetected. The ground-breaking part of our research occurred when our antibodies were shown to attach to ATTR amyloid plaques and initiate immune clearance while preventing further plaque growth.

“While some drugs suppress the production of amyloid, the antibodies we found actually clear the misfolded proteins and tag the deposits for immune destruction,” says Chakrabartty.

Since then, we have joined forces with Prothena Life Sciences a biotechnology company who is helping us bring this drug to market safely. A monoclonal immune therapy , PRX004, that came out of this collaboration is currently in the first phase of its clinical trial, which if successful, could provide those with ATTR amyloidosis with a non-invasive treatment that will largely improve standard of life and life expectancy of those with the disease.

Dr. Chakrabartty In The News

Published References for additional reading:

  1. Gertz, Morie A., et al. Diagnosis, Prognosis, and Therapy of Transthyretin Amyloidosis. Journal of the American College of Cardiology, 66 (21), 2015, 2451–2466., doi:10.1016/j.jacc.2015.09.075. [1]
  2. Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis 2013; 8(31).[2]
  3. Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation 2012; 126:1286–300
  4. Rappley, Irit, et al. Quantification of Transthyretin Kinetic Stability in Human Plasma Using Subunit Exchange. Biochemistry, 53 (12), 2014, 1993–2006., doi:10.1021/bi500171j. [4]
  5. Higaki, Jeffrey N, et al. Novel Conformation-Specific Monoclonal Antibodies against Amyloidogenic Forms of Transthyretin. Amyloid, 10 (1), 16 Mar. 2016, doi:10.1186/1750-1172-10-s1-p1. [5]
  6. Galant, N.J., et al. 2016. Sub-stoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses. Nature Scientific Reports. 6. [6]

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