Sanford-Burnham’s co-founder Lillian Fishman celebrated her 98th birthday this past weekend. In an interview conducted by Patty Fuller for U-T San Diego, Mrs. Fishman recounts the Institute’s beginnings in 1976 as the La Jolla Cancer Research Foundation, and explains the development of San Diego’s scientific communities over the past four decades.
Today we held our fourth annual symposium marking Rare Disease Day. As keynote speaker William A. Gahl, M.D., Ph.D., noted, “it takes a village” to diagnose, treat, and care for people with rare diseases. By “village,” he meant parents, advocates, doctors, basic scientists, clinical researchers, government officials, and philanthropists—all of whom were represented at the event. Gahl is clinical director of the National Human Genome Research Institute (NHGRI) and director of the NIH Undiagnosed Diseases Program
Editor’s note: this is the second in a series of posts highlighting drug screening studies in our Conrad Prebys Center for Chemical Genomics. Read the first post here.
Calcification of the medial layer of arteries is increasingly recognized as an important clinical problem. Medial vascular calcification (MVC) is the major cause of morbidity and mortality in generalized arterial calcification of infancy (GACI), and contributes to cardiovascular deterioration in Kawasaki disease (KD), chronic kidney disease (CKD), as well as in diabetes, obesity, and aging. MVC is thought to result from decreased circulating levels of the mineralization inhibitor, inorganic pyrophosphate (PPi).
Researchers at Sanford-Burnham have revealed that the development of MVC in mouse and rat models is accompanied by up-regulation of tissue-nonspecific alkaline phosphatase (TNAP), an enzyme whose primary function is to hydrolyze PPi, and thus, crucial in determining where mineralization occurs. Preliminary data have proven that upregulation of TNAP is sufficient to cause MVC and Sanford-Burnham scientists have developed potent drug-like inhibitors of TNAP.
José Luis Millán, Ph.D. and his lab have studied hypophosphatasia, an inherited disease that makes bones dangerously fragile, for the past 15 years. The researchers developed a mouse model of the disease—mice that, like their human counterparts, lack an enzyme called alkaline phosphatase. Then, just about five years ago, scientists from Enobia Pharma approached Millán. They had developed an enzyme replacement therapy called ENB-0040 and they needed someone who could help them test it—someone with a model and with extensive knowledge of hypophosphatasia and the alkaline phosphatase enzyme. So Millán and his team administered it to their mice. Mice with hypophosphatasia usually survive for 20 days at most. When the treated mice were alive at day 21, Dr. Millán knew they were onto something promising.
For nearly 250 years, generations of scientists believed that the older an animal gets, the less able it is to regenerate and replace damaged or diseased tissue. (Even Charles Darwin weighed in.) Everyone assumed that, as animals age, cellular resources become exhausted, DNA repair mechanisms break down, healing takes longer and tumors develop. As of today, however, that’s no longer the doctrine. It still might be harder and harder for humans to repair wounds and heal as we age, but it turns out that the humble newt is another story.
When injured, newts can regenerate limbs, tails or eyes right back to factory standards. Humans can only do that at the very tip of the finger and only under very limited circumstances. And according to a new study published today in the journal Nature Communications, old newts can do it just as well as young newts. The study focused on the newt’s optical lens, which can be removed entirely and, after the incision heals, completely regenerate in a single day. The study’s lead author, Dr. Goro Eguchi, began breeding newts and collecting lenses 16 years ago. Throughout the years since, lenses were removed 18 times from the same animals. By the time of the last tissue collection, they were at least 30 years old (very old, for a newt).
This video of three year-old Corinna is remarkable because it would seem so unremarkable if you didn’t know Corinna’s story—she looks just like any other kid. I had the pleasure of meeting this very special attendee at Sanford-Burnham’s 2nd Annual Rare Disease Day Symposium last February. Corinna was born with hypophosphatasia (HPP), a rare inherited disease that affects bone development, leaving her fragile and unable to walk. Lauren, Corinna’s mother, had brought her along to the symposium and was excited to meet the scientists studying HPP and hear about the latest research.
The family traveled from Philadelphia to be there that day – no small task, considering Corinna’s special needs and lack of mobility. I first talked to Lauren on the phone, helping her with directions from her hotel to the Sanford-Burnham campus. Then I waited for them outside and helped her get the stroller out of the taxi. I set it up while Lauren got Corinna out of the car. Corinna was blond, adorable, friendly—and just about the same size as my own daughter. My heart went out to them. I know how trying it can be to travel with a toddler, even under the best of circumstances.
There was a moment at our recent Rare Disease Symposium when Dr. Michael Whyte, a pediatrician from Shriner’s Hospitals in St. Louis, presented video of a patient who is participating in a clinical trial. The patient, Amy, suffers from hypophosphatasia (HPP), a genetic bone disease similar to rickets. The trial is for an enzyme replacement therapy developed collaboratively by Dr. Whyte, Dr. José Luis Millán and Enobia Pharma to treat HPP. Before treatment, Amy’s bones were so soft she had to be flown to the trial in an insulated box. She was weeks away from dying. In the video, she runs, jumps and kicks a ball. Hard not to be moved.
Enobia’s HPP drug is in Phase II clinical trials and looks quite promising. However, rare diseases present a difficult problem. While relatively few people suffer from any single rare disease, there are thousands of these conditions. Large pharmaceutical and biotech companies have a difficult time addressing them because they have not figured out how to make back their investments. But the issues go even deeper. How do you conduct a robust clinical trial on a new treatment when only a handful of people need to be treated? And how do you balance the regulatory environment to ensure that new, safe treatments can reach patients? In fact, how do you even diagnose a rare disease when so few physicians have any experience with it?
Today is Rare Disease Day and Dr. José Luis Millán, a professor in our Sanford Children’s Health Research Center, held a live chat on hypophosphatasia(HPP), a rare, genetic bone disorder similar to rickets. HPP patients’ bones do not mineralize properly. In some cases, a patient’s bones are so soft they can barely be touched without breaking.Dr. Millán has been working for several years with Dr. Michael Whyte, of Shriners Hospitals for Children in St. Louis, and Enobia Pharma to develop an enzyme replacement therapy for HPP. Though still in clinical trials, the treatment has so far shown dramatic results. In some cases, children who probably would not have survived without treatment can now run, jump and develop normally.
In 2008, a young child, known simply as Baby Amy, was flown from her home in Ireland to Winnipeg, Canada to be treated for Infantile Hypophosphatasia (HPP) a horrible – often fatal – disease that makes bones dangerously fragile. The results were striking. On the way to Canada, Baby Amy was transported in an insulated box to prevent her bones from breaking. On the way home, after receiving an enzyme replacement therapy (a drug called ENB-0040), she was healthy enough to be held by her mother. Dr. José Luis Millán, a professor in the Sanford Children’s Health Research Center at Sanford-Burnham had worked closely with ENOBIA Pharma and Dr. Michael P. Whyte of Shriner’s Hospital for Children in St. Louis to create this first-ever treatment for HPP. He was understandably thrilled.
By Claire Attwooll
Recently, Sanford-Burnham hosted our inaugural Rare Disease Symposium, using a unique format in which patients and their families were given a voice—and the scientists were there to listen.
“What we hoped to achieve was to open the lines of communication between researchers, patients, families and advocacy groups,” said symposium organizer Dr. Hudson Freeze. “We can learn so much from these families, and then we can give something back.”
Diseases are classified as “rare” when they affect fewer than 200,000 people in the United States. But there are around 7,000 such disorders, and 30 million Americans are affected. Because of these diseases’ rarity, patients and their families often struggle to find information, and many have started advocacy groups to raise awareness and reach out to other families who need help. These families can be a great help to researchers, having gained personal Ph.D.s in the intricacies of an uncommon disease.