Trial Information

High-Tc Susceptometer to Monitor Transfusional Iron Overload (NSR Device)

This project will validate our new high-transition-temperature (high-Tc; operating at 77°K,
cooled by liquid nitrogen) superconducting magnetic susceptometer as the most clinically
effective means for monitoring iron overload in patients who require chronic red blood cell
transfusion. Transfusional iron overload is an orphan disease that develops in patients who
require regular blood transfusions for treatment of a variety of refractory anemias that are
themselves orphan disorders, including sickle-cell disease, thalassemia major (Cooley's
anemia), Diamond-Blackfan anemia, aplastic anemia, pure red cell aplasia, hypoplastic and
myelodysplastic disorders. In the United States, the number of anemic patients with
transfusional iron overload is estimated to be less than 50,000. Without iron-chelating
therapy, potentially lethal amounts of iron accumulate in these patients. Because the body
lacks an effective means to eliminate excess iron, the iron contained in transfused red
cells is progressively deposited in the liver, heart, pancreas and other organs. Cirrhosis,
heart failure, diabetes and other disorders develop. Treatment with a chelating agent
capable of sequestering iron and permitting its excretion from the body provides a means of
managing transfusional iron overload that can prolong survival and avert or ameliorate
iron-induced organ damage. Two iron-chelating agents are now approved for use in the U.S.
for the treatment of transfusional iron overload: (1) deferoxamine B (Desferal®), a
parenteral agent in use for almost four decades, and (ii) deferasirox (Exjade®), an orally
administered agent introduced in 2005. With both chelators, optimal management of patients
requires careful monitoring of body iron to prevent iron-induced toxicity while avoiding
adverse effects of excessive chelator administration. Our laboratories originally proposed
that storage iron (ferritin and hemosiderin) could be non-invasively assessed in vivo by
measurement of magnetic susceptibility. We subsequently developed low-transition-temperature
(low-Tc; operating at 4°K, cooled by liquid helium) superconducting quantum interference
device (SQUID) susceptometry as a clinical method for quantitation of hepatic iron stores.
The transition temperature is the temperature at which the electrical resistance of a
superconducting material drops to zero. The safety, ease, rapidity and comfort of magnetic
measurements have made frequent, serial investigations technically feasible and practically
acceptable to patients. Susceptometry permits accurate, direct, reliable, and repeated
measurements of hepatic iron stores. Despite these advantages, the cost (about $1,000,000
per device), instrumental complexity and need for liquid-helium cooling of the low-Tc
susceptometers restricted clinical adoption of the method. Worldwide, only four low-Tc
susceptometers have been used clinically (in New York, Oakland, Hamburg and Turin).
Recently, with the support of a Bioengineering Research Partnership Grant (R01 DK057209), we
have made a series of technological breakthroughs and instrumental innovations that have
made possible replacement, redesign and refinement of the elements of the low-Tc
susceptometer, operating at 4°K in liquid helium, with components able to function at 77°K
in liquid nitrogen. This new high-Tc susceptometer, the first medical device utilizing the
phenomenon of high-temperature superconductivity, is an inexpensive instrument that can
easily be used in a hospital environment. These Phase 2 clinical studies are designed to
test the hypothesis that measurements of hepatic iron stores with our new high-Tc
susceptometer are clinically superior to all other available methods and to supply essential
data needed for FDA approval of the medical device. The proposed project has three specific
aims:

1. to calibrate the high-Tc susceptometer with the results of biochemical analysis of
tissue from liver explants from adult and pediatric patients undergoing liver
transplantation and from clinically indicated liver biopsy; and

2. to prospectively validate the high-Tc susceptometer using the results of biochemical
analysis of tissue from liver explants from adult and pediatric patients undergoing
liver transplantation and from clinically indicated liver biopsy; and

3. to prospectively compare measurements of hepatic iron concentration by the high-Tc
susceptometer with (i) estimates derived from liver magnetic resonance imaging (MRI)
relaxation rates (R2, R2*, signal intensity ratios), (ii) with determinations of serum
ferritin, and (iii) with histopathological examination, using biochemical analysis of
liver storage iron concentrations as the reference standard.

FDA approval of an affordable, readily usable instrument for the non-invasive measurement of
hepatic iron stores would lead to major advances in the management of patients with
transfusional iron overload that would find immediate and widespread clinical use both in
the U.S. and worldwide.