Yale Professor Develops “Superhuman” Enzymes Into Therapy for Rare Infant Disease

When Yale Professor Demetrios Braddock came to the university more than a decade ago, his research focused on one particular family of enzymes called ENPP1 that exhibited extraordinary properties. “I was struck by how stable they were,” Braddock says. “They could be purified and put in a refrigerator for a year; they could be frozen and thawed and still be active. They had superhuman qualities.”

These exceptional characteristics provided the substrate for additional protein engineering required to convert the enzyme into a drug. Dr. Braddock’s team first modified the membrane-bound enzyme into a soluble protein, and then created a fusion protein to increase the pharmacokinetic properties of the final drug.

Now investors are betting that Braddock’s discovery holds the key to reversing the effects of a rare disease impacting infants called generalized arterial calcification of infancy or GACI for which there is no viable treatment. Inozyme Pharmaceuticals, the startup developing this new therapy, recently received a $49M funding round from Sanofi, Novo Nordisk and two additional venture firms.

GACI is a devastating ultra-rare genetic disease, meaning one that affects just a few thousand patients worldwide. Children with the disorder have low levels of an enzyme that stops calcium from building up in their blood vessels. Most will die within three months. Those that do survive will acquire bone-wasting rickets disease. “It’s a yin and yang,” Braddock says. “The body over-calcifies and then under-mineralizes.”

The enzymes Braddock was studying are directly related to the mutations evident in these patients and as such made for a perfect target for translational work. And when mice with GACI were given a replacement version of the enzyme, it helped to reduce the calcifications and prevented the animals from dying. His findings were published in Nature Communications.

Braddock has worked closely with the Yale Office of Cooperative Research (OCR) in developing his research to the point where it was ready to be commercialized. “I can’t overstate the importance of OCR’s role in directing me and supporting me until I got to this stage,” he says. Braddock adds that once you have proof of concept, “your best advocate is yourself and the team of people you put together.”

According to David Lewin, Sr. Associate Director of Business Development with OCR, “Dr. Braddock is the consummate team player. He is consistently clear and open with his peers, investors and the business development professionals who have contributed, supported, and invested in his research programs. It is gratifying to be part of the team that has resulted in the founding of Inozyme. We are also grateful to the State of Connecticut, through the offices of Connecticut Innovations and their Connecticut Bioscience Innovation Fund (CBIF) which supported Dr. Braddock’s research.”  

“Dr. Braddock’s work is a great example of strong research that has resulted in a commercializable innovation,” says Dan Wagner, Managing Director of Investments at Connecticut Innovations. “This is truly the reason CBIF was created and we look forward to Inozyme’s continued success in the future.”

It was 12 months between publishing in Nature and the funding round – a year during which Braddock pulled together a powerhouse team that includes Joseph Schlessinger, William H. Prusoff Professor and Chairman of the Department of Pharmacology at Yale University School of Medicine and founder of Kolltan; and Enrique M. De La Cruz, Professor of Molecular Biophysics and Biochemistry at Yale. Braddock says he and Inozyme cofounder and CEO Axel Bolte traveled extensively to pitch the startup and the promise of their lead therapy, INZ-701, designed to treat the lead ultra-rare indication. In addition, Inozyme is exploring optimized enzymes for use in common diseases of mineral imbalances, including chronic kidney disease, which affects 31 million Americans and can lead to calcification in the veins and arteries.

“We put together a plan to bring our drug through a Phase II trial and were able to do it to the satisfaction of the VCs and their advisors,” Braddock says. 

He admits it was a grueling process, but the encouragement of an experienced faculty entrepreneur like Schlessinger helped pull him through. “He was very encouraging,” Braddock says of his colleague and business partner. “That’s what Yale offers – it’s collegial, there are no walls, we all work together.”

CONTACT: Brita Belli, Communications Officer, Yale Office of Cooperative Research, (203)804-1911, brita.belli@yale.edu.