Doctoral Dissertations

Date of Award

5-2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Jonathan S. Wall

Committee Members

Stephen Kennel, Robert Donnell, Stephen Kania

Abstract

Amyloidosis is a degenerative protein misfolding disorder that leads to the extracellular accumulation of amyloid deposits containing protein fibrils, heparan sulfate proteoglycans, glycoproteins and apolipoproteins. To date, at least 27 proteins have been identified as components of pathologic amyloid fibrils. In systemic forms of the disease, amyloid deposits can evade the immune system and expand throughout various tissues. As the deposits grow, tissue architecture is disrupted, leading to organ dysfunction and death.

In the US, there are ~3500 newly diagnosed patients with amyloidosis annually. The deposition of light chains as amyloid (AL amyloidosis) is the most common form of visceral disease. The prognoses for patients varies (median survival for AL 12-40 months), but those with cardiac involvement have a considerably less favorable prognosis (~9 months median survival). Many researchers and physicians believe that early detection of amyloidosis could improve patient survival. The current gold standard for diagnosis involves histological examination of biopsy-derived tissue specimens. This method is invasive, subject to sampling error, and can be quite challenging. In an attempt to facilitate diagnosis, molecular imaging techniques using amyloid-reactive tracers have been developed such that a whole body, non-invasive “picture” of amyloid burden in patients may be established. There are several imaging agents used clinically world-wide, but each of these has limitations regarding its adoption in the US (i.e. 123[123]I-SAP is not FDA-approved and cannot image cardiac amyloid deposits, 124[124]I-11-1F4 only images ~60% of patients, and 99m[99m]Tc-labeled bone-seeking agents cannot image the most common forms of amyloid disease in patients). Given these limitations, there is an unmet clinical need for a facile method of quantitatively detecting whole body amyloid burden in patients.

To this end, we have developed synthetic, pan-amyloid-reactive peptides for use as radiotracers by using SPECT/CT or PET/CT molecular imaging to non-invasively detect whole body amyloid load in patients. Through numerous preclinical experiments using ex vivo and transgenic murine models of amyloidosis, the structurally related peptides were found to have unique in vivo characteristics. Our findings suggest that, if further optimized, certain peptides could have clinical merit for the early detection of multiple types of amyloidosis.

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