Target unique genetic diseases through common pathways

As a former gene therapy researcher, I have been disappointed by nearly all attempts at gene therapy for genetic disorders. Our immune system is its own worst enemy as far as gene therapy goes, clearing attempts to introduce new genetic material into cells and organs without breaking a sweat. As a grad student I was fond of saying, “Gene therapy attempts to treat disorders we don't understand in systems we don't understand using gene vectors we don't understand.”

A dozen years ago, many expected gene therapy to be a medical Hail Mary. Surely something good would come out of the considerable efforts directed at gene replacement-based therapies. Today, the prospects for successful primary gene therapy for most disorders still remain distant. However, remarkable gains fueled by genomic discoveries have been made in understanding the pathophysiology of many genetic disorders, and are slowly yielding therapeutic breakthroughs.

A particularly compelling story is the evolution of our understanding of Marfan syndrome. Marfan syndrome is caused by mutations in the fibrillin-1 (Fbn 1) gene that encodes the protein fibrillin 1, a constituent of the extracellular matrix in connective tissues, including blood vessel walls. It is one of the classic autosomal dominantly inherited disorders characterized by tall stature, disproportionately long limbs, dislocated lenses of the eye, and other connective tissue abnormalities. The most devastating consequence of the disorder is a predisposition to aortic root dilatation and aneurysm formation that all too frequently leads to death in early adulthood.

Until the last few years, most investigators thought that Marfan syndrome was a near-hopeless case for targeted therapeutic interventions, largely because the defect was in a structural protein rather than in an enzyme. In general, it is comparatively easy to come up with rational ways for treating disorders with enzyme replacement but much harder to conceptualize rescuing a disorder if the cause is a structural element defect. Marfan syndrome patients were therefore relegated to risky surgical correction of developing vascular abnormalities, or to marginally beneficial use of beta-blockers to slow blood vessel dilatation.

Not satisfied that a classical structural protein defect could explain all of the features of Marfan syndrome, investigators made a key discovery a few years ago. Defects in Fbn-1 cause disregulation of transforming growth factor beta (TGF-beta) signaling in affected tissues. Using mouse models for Marfan syndrome and TGF-beta neutralizing antibodies, researchers were able to show rescue of the blood vessel abnormalities.

This is itself is a remarkable scientific finding, but delivering antibodies over a long period to patients isn't a very appealing clinical solution. Then something bordering on magical happened. A group of very clever investigators recognized that an already commonly used antihypertensive in the class of drugs known as angiotensin II type 1 receptor blockers (ARBs) also interfered with TGF-beta signaling and they tried the drug in the mouse Marfan model. The results, published in Science in 2006, were nothing short of spectacular—the vascular consequences of the Marfan syndrome could be prevented in the mouse model system.

This notable success, coupled with the grave prognosis for Marfan syndrome and the known safety profile of the ARB drugs, has led to a large prospective human clinical trial. Preliminary results have been promising, and many in the field are anticipating that the trial will show clear, major benefit from the use of ARBs.

It is interesting, and probably prophetic, that Marfan syndrome treatment soon may be revolutionized through a careful tweaking of a formerly unrecognized important pathway rather than through brute-force correction of the underlying genetic defect. Expect that this will be the model for other formerly truculent genetic disorders.