Fall 2016

The gene team

Scientists bring 20-year collaboration to Pharmacy School

Feature Image
Ryan Tobin
Kanneboyina Nagaraju, left, is chair of the Department of Pharmaceutical Sciences. Eric Hoffman is associate dean for research of the School of Pharmacy and Pharmaceutical Sciences.

Next fall, the first cohort of graduate students will begin classes at the Binghamton University School of Pharmacy and Pharmaceutical Sciences. They will be met by a pair of nationally recognized geneticists, leaders in muscle disease research, who will guide them through the fine points of pharmacological research and, in the process, teach them much about what it means to be colleagues, mentors and friends.

“This is very exciting. We’re starting with a blank slate, and our goal is to place the department in the top 10 programs nationally within 10 years,” says Kanneboyina Nagaraju, chair of Binghamton University’s new Department of Pharmaceutical Sciences. 

Such is the ambitious goal outlined by Nagaraju [“Raju”] and his mentor and research collaborator, Eric Hoffman, associate dean for research of the new School of Pharmacy and Pharmaceutical Sciences. They’ve been working together on translational research in muscle disease for more than 20 years. This fall they are moving their research shops to Binghamton, as well as hiring the faculty who will develop new drugs and train the next generation of pharmacists.

“I think the key feature of any working relationship is trust. In our individual domains of expertise, we fundamentally believe that what the other person is doing is almost certainly the smart and appropriate thing to do, whether we fully understand the fine details, or not,” Hoffman says. “Together, we cover different aspects of the ‘idea lifecycle.’”

The two value the complementary nature of their relationship. “Raju is a better scientist than me,” Hoffman says. “He’s very methodological in his thinking, very analytical and well-read.” He calls his colleague the “affable engineer of the research machine.”
Nagaraju agrees: “I’m detail-oriented — I’m handy and make things happen.”

Conversely, Nagaraju views Hoffman as exceptionally bright, a “visionary who sees things 15 or 20 years out.”

“He has mind-boggling ideas and draws connections between concepts in a remarkable way,” Nagaraju says.

Hoffman says his strength is in interdisciplinary and collaborative research. “[I’m] good at forming and managing interdisciplinary teams — and [developing] seemingly disparate observations into innovative models. 

“I have a music degree,” he says, “and I often treat science like a music project — taking different themes and variations, synthesizing them into different patterns that resonate with me and the audience of ‘science.’ Often, great music involves an orchestra, as interdisciplinary research requires a team.”

The two come to Binghamton with a wealth of experience and an international standing as pioneers in the genetic causes of disease. Together, they’ve co-authored 48 papers while raising more than $150 million in research grants. Currently they are working to develop a drug that will alleviate the worst symptoms of a deadly disease — Duchenne muscular dystrophy.

Finding a gene and a friend

Hiring them is a coup for the School of Pharmacy and Pharmaceutical Sciences and bodes well for its future, says Founding Dean Gloria Meredith. “Hoffman and Nagaraju are experts in molecular genetics and immunology. Their understanding of disease mechanisms in general, and the tools they use in their research, precisely match our requirements.”

Together, they have established a reputation in their field that immediately raises the school’s profile. Hoffman was a member of the team of researchers, led by Louis Kunkel at Boston Children’s Hospital at Harvard Medical School, that in 1986 established a milestone in genetic research by identifying the gene responsible for causing Duchenne muscular dystrophy, a rare (or “orphan”) disease affecting about 1 in 3,600 children, almost all of them boys.

The following year, Hoffman was the lead researcher on a paper showing that this gene was responsible for the production of the dystrophin protein, a component of muscle that helps cells recover and regenerate. Duchenne patients are unable to produce the dystrophin protein and gradually lose muscle, typically succumbing to the disease in early adulthood. Hoffman has since focused much of his research on understanding the disease and developing drugs to slow or stop it.

Professionally, Hoffman has held positions at some of the most prestigious institutions engaged in genetic research. In addition to his time at Children’s Hospital, he taught molecular genetics at the University of Pittsburgh School of Medicine, served as director of the Center for Genetic Medicine at the Children’s National Medical Center in Washington, D.C., and chaired the Department of Integrative Systems Biology at George Washington University School of Medicine.

Since he began working with Hoffman in 1996, Nagaraju’s research has complemented that of his co-researcher. Trained in India in veterinary medicine (DVM, MVSc) and immunology (PhD), his research focuses on genetic and autoimmune muscle diseases, though his emphasis is on immunology and the development of transgenic (genetically modified) mouse models that are critical for understanding the purpose of individual genes and testing possible therapeutic approaches. 

“Raju asked for some help on one of his projects more than 15 years ago,” Hoffman says, “and the more we learned of each other’s research, the more our projects seemed naturally synergistic, so what started as a little help became long-term collaborations.”

Nagaraju says Hoffman underestimates the “little help.” In one of his first research projects as a junior faculty member at Johns Hopkins University School of Medicine, Nagaraju was investigating why certain autoimmune diseases occur more in females of childbearing age than males. He designed an experiment in mice to understand the gene expression differences as a function of puberty. He thought Hoffman could help him understand what was taking place at the genetic level in the samples that he’d collected.

Hoffman agreed to look at the samples, and Nagaraju sent him every one he’d collected, 50 in all. But in his excitement, Nagaraju neglected to ask the cost of the analysis. 

The bill was a big surprise.

In the early days of gene expression profiling, genetic testing was difficult and expensive — more than a thousand dollars per sample. The single experiment threatened to deplete Nagaraju’s meager faculty funds. “I was panicking. I didn’t know what to do. But when I explained the situation to Eric, he agreed to forgive much of the cost of the project so the research would continue.”

Thus began a decade of intermittent collaboration. Nagaraju says he was “deeply influenced by Hoffman’s exceptional scientific knowledge and innovative approaches to research — but most of all by his kindness and generosity to people.” So it was an easy decision to make when, in 2005, Hoffman suggested Nagaraju join him at Children’s National Medical Center.

But it’s not all business for the pair. Often, their families spend time together, and the two take time to work together at an orchard that Hoffman owns in Nova Scotia. “We call it ‘executive work experience,’” Hoffman says. Nagaraju relishes the opportunity to return to rural life. “I was raised in a village in southern India, and I like to get my hands dirty. We don’t talk science when we are farming, but I learn from him — he’s like my big brother.”

Binghamton offers room to grow

A similar dynamic brings them to Binghamton where, Hoffman says, “The more I learned, the more I liked the idea of starting from the ground up — the focus on drug development in a time of needed change, a new building, new research programs, great engineering and nursing schools to collaborate with, and a focus on academic spinoffs.”

Plus, he says, he was impressed by the University’s “Yes, we can make this work” attitude.

Nagaraju says his priority is to make a difference. “I figured I had a better chance of accomplishing this if I continued to work with Eric.”

Both men cite “making a difference” as the driving force behind their research, which they will continue at Binghamton. Along with John McCall, a medical chemist with extensive experience in the pharmaceutical industry, including Upjohn, Pharmacia and Pfizer, they have been working to develop a drug, Vamorolone (or VBP-15), that would dramatically reduce side effects from treatments for those suffering from Duchenne muscular dystrophy while improving muscle strength.

The standard treatment is to provide large doses of steroids, such as prednisone, which reduce the pace of muscle deterioration. Unfortunately, this treatment has significant side effects, including bone fragility, weight gain, stunted growth and insulin resistance.

Vamorolone reduces these side effects by fine-tuning the chemistry and activities of the steroid. “Think of prednisone as an onion, with good layers (efficacy) and bad layers (safety problems),” Hoffman says. “[We] systematically peeled away the layers of the corticosteroid onion, then created a new drug that kept and improved the good, but removed the bad layers.”

Vamorolone recently completed Phase I testing (in healthy adults), showing that the drug successfully reduced or eliminated many side effects associated with corticosteroids. Phase II clinical trials have now begun in boys with Duchenne, but Hoffman is hopeful that the drug might help treat other pediatric diseases that rely on high doses of steroids for treatment, such as asthma, arthritis, sickle cell anemia and cystic fibrosis.

Excited about the potential for this new “dissociative steroid,” Hoffman, Nagaraju and McCall have established a company called ReveraGen BioPharma to support development and testing. It is their first biotech spinoff and has raised $24 million in capital.

Hoffman, Nagaraju and their research teams have played significant roles in developing other approaches to Duchenne therapy. One, currently in clinical trial, masks or “skips” the defective part of the gene, allowing it to perform its task at normal or near-normal efficiencies. This approach, called exon skipping, partially repairs the dystrophin gene (essentially turning it into another, less severe, form of dystrophy called Becker’s). It could help patients live longer and with a better quality of life.

The treatment uses an oligonucleotide drug, short sections of DNA or RNA molecules that are injected into the subject. Hoffman established a proof of principle of this approach in dogs with muscular dystrophy, together with collaborator Shin’ichi Takeda in Japan. When Nagaraju first saw a video of the dogs under treatment, he was astounded. “I couldn’t believe it — the dog — it walked very poorly before the injection, but now it was jumping and jumping and jumping. It was something I could not have imagined.”

Nagaraju and Hoffman have established a second spinoff company, AGADA Biosciences, a clinical research organization that provides services to other companies to support their drug development programs. “Many of the companies that are working in this field find it too expensive to develop their own drug research centers and run tests, so we help them,” Nagaraju says.

The researchers will be splitting their time between the University and their businesses, with clear lines between the two. Indeed, the University is excited about the work that the companies are doing, and want other faculty in the school to follow this model.

“Startup enterprises enhance the University’s economic impact in the community,” Meredith says. “We encourage new research enterprises collaborating with existing companies, and Hoffman and Nagaraju’s experience with startups will be a great benefit to the faculty.”

Both men will also work directly with graduate students, who are already beginning to apply for classes that will begin next year. For now they are busy hiring faculty, establishing their laboratories and developing curricula.

“The idea is very simple,” Nagaraju says. “In my own life I may never find anything remarkable or world-changing — but if I train hundreds and hundreds of students, I am amplifying by many times my chance of success. This is why we are in the business of teaching.”