Cobinamide as a disease-modifying treatment for Marfan Syndrome: optimizaation of absorption

Project Summary
Marfan Syndrome (MFS) is a genetic disorder with a prevalence of ~1 in 5,000 people. Aneurysms in the
ascending aorta are the most serious manifestation of the condition and can lead to sudden death due to
spontaneous rupture. The aneurysms are due in part to increased oxidative stress in the smooth muscle cells of
the aortic wall. Existing medical treatments are not disease-modifying and are only partially effective. Surgical
aneurysm repair is the only proven method to prevent death.
Cobinamide is the penultimate precursor in the biosynthesis of vitamin B12 (cobalamin). We have shown
recently that cobinamide is a powerful and versatile antioxidant, more potent than other well-known antioxidants
and able to neutralize both reactive oxygen and reactive nitrogen species. When administered as
bis(histidyl)cobinamide in drinking water, cobinamide prevented aortic dilation and abolished oxidative stress
and pathological changes in the aorta of mice with a mutation in fibrillin-1, analogous to mutations that occur in
Marfan patients. Cobinamide thus has the potential to be a disease-modifying treatment for MFS.
Under a Phase I SBIR grant, we found that bis(histidyl)cobinamide has low bioavailability, only 0.8% was
absorbed after oral administration. The goal of the current project is to increase intestinal absorption of
cobinamide to make it a more practical therapy for conditions like MFS where long-term treatment is needed.
This will be accomplished by varying the ligands coordinated to the central cobalt atom of cobinamide and by
using permeation enhancers. Bis(histidyl)cobinamide is hydrophilic with a low log P value, retarding its
movement across cells. Hydrophobic ligands can increase the hydrophobicity/lipophilicity of the resulting
cobinamide complex, and we found that a phenyl-containing ligand increased cellular uptake of cobinamide and
cobinamide bioavailability ~2-fold compared to bis(histidyl)cobinamide. We now plan to test a variety of
hydrophobic ligands, with the intent of finding ligands that increase cobinamide permeation through a human
intestinal tissue model (EpiIntestinalTM) 4-5-fold compared to bis(histidyl)cobinamide. We will then combine these
liganded cobinamide complexes with a permeation enhancer. Chitosan, a well-known permeation enhancer,
increased cobinamide absorption across mouse gingiva, and salcaprozate sodium, another permeation
enhancer, increases intestinal vitamin B12 (cobalamin) absorption. We will test these and other enhancers, with
the overall goal to increase cobinamide permeation through EpiIntestinalTM by 8-10-fold compared to
bis(histidyl)cobinamide. We will then evaluate bioavailability of the top performing cobinamide formulations
(complex-enhancer combinations) in rats, with the goal of finding one or more formulations that yields a
bioavailability of ≥6% in male and female animals. A number of drugs have bioavailabilities ranging from 1-10%.

Grant Number: 1R61HL175687-01A1
NIH Institute/Center: NIH
Principal Investigator: GERRY BOSS