Revel Pharmaceuticals

Born out of research funded by Lifespan Research Institute at the Spiegel lab at Yale University, Revel Pharmaceuticals is developing rejuvenation biotechnologies to address the stiffening and dysfunction of arteries and other tissues with age caused by Advanced Glycation End-products (AGE).

The long-lived collagen proteins that give structure to our arteries, skin, and other tissues are constantly exposed to blood sugar and other reactive molecules in the bloodstream. These sugar molecules can sometimes bind to collagen and form initially-reversible adducts that — if not reversed — can mature into AGE that alter the physical properties of tissues and cause inflammation. AGE crosslinks, in particular, bind adjacent collagen strands together and so limit their motion, are thought to contribute to the gradual stiffening of tissues, in particular blood vessels. This crosslinking is thought to contribute  to increasing arterial stiffness and systolic blood pressure, resulting in kidney damage, heart failure, and an increased risk of stroke.

The most common of these crosslinks is thought to be the AGE known as glucosepane. With LRI funding, the Spiegel lab developed a convenient method to synthesize glucosepane, enabling the development of glucosepane-cleaving drugs. Such drugs would break apart glucosepane crosslinks and thus liberate arterial collagen strands to move independently again, restoring youthful arterial function. Moreover, the Spiegel and Clark labs used synthetic glucosepane to develop anti-glucosepane antibodies that would allow researchers to study the accumulation of glucosepane in tissues with age and test the level of it in tissues before and after treatment with candidate AGE-cleaving drugs.

With a ready supply of glucosepane on hand, Revel seized upon the emerging techniques of metagenomic libraries to look for bacterial enzymes capable of cleaving it. This technique allowed Revel scientists to screen the vast, uncharacterized enzymatic armamentarium of unidentified, uncultured environmental bacteria with an efficiency approaching the high-throughput methods used for conventional small-molecule drugs. In 2018, they reported finding bacterial enzymes that could break down glucosepane crosslinks. The company had intended to modify these enzymes into forms that would be suitable for new longevity therapeutics. However, they have had difficulty reproducing this original finding.

Recently, Revel discovered an enzyme capable of oxidizing carboxymethyl-lysine (CML) off of tissue lysine residues. CML is a common adduct in many aging and diabetic tissues, including being the most significant non-crosslinking AGE in the eye. Revel is working with this enzyme on two tracks. First, they are working to use it to develop enzymes to test for CML levels in tissues for experimental and diagnostic use and to assess the effects of CML-cleaving therapeutics. Secondly, they are working to use it as the basis of those very therapeutics.

Specifically, CML and other AGEs have been implicated in the vascular and inflammatory complications of diabetes, including diabetic retinopathy (DR). The mainstay of therapy for diabetic macular edema (DME — the advanced, vision-threatening stage of DR) is targeting vascular hyperpermeability using antibodies against the blood vessel growth-promoting molecule VEGF, but only half of people suffering with DME enjoy a clinically-appreciable benefit from this therapy. Revel is working to engineer CML oxidase into a candidate that could efficiently cleave CML adducts from retinal tissues. Cleaving CML in the diabetic eye might have a true disease-modifying effect, preserving and restoring the structural integrity and function of the diabetic retina.