Disease foundations team up with HSCI to hasten cures

Whether studying the fundamental properties of stem cells or screening disease-specific stem cells to search for potential therapeutics, all HSCI researchers share a common goal—to find cures for many pernicious diseases, both common and rare, as quickly as possible.

Considering HSCI's unique bench-to-bedside focus, it is not surprising that a number of disease foundations—non-profit organizations whose mission is to find cures for specific diseases— have made significant commitments to fund research by HSCI scientists.

Indeed, since HSCI's inception six years ago, disease foundations have invested or committed more than $14 million to HSCI for research in areas that span many diseases, including ALS (Lou Gehrig's disease), diabetes, Huntington's disease, muscular dystrophy, and spinal muscular atrophy. The importance of this type of support to HSCI's work cannot be overstated, particularly in today's fiscal environment, where competition for federal research dollars is especially intense and industry focuses largely on funding late-stage research for prevalent diseases.

"Often disease foundations are founded by people whose families have been affected by a devastating condition, so they share our passion for finding cures as quickly as possible and are excited about the promise of stem cell research to achieve that goal," says Brock Reeve, HSCI's Executive Director. "The support of disease foundations has been critical to HSCI, filling a funding gap that has enabled our scientists to make significant, measurable progress against some truly devastating diseases, especially orphan diseases that might otherwise be ignored."

Targeting SMA: the SMA Foundation

One such disease is spinal muscular atrophy (SMA), an inherited childhood neuromuscular disorder in which nerve cells in the spinal cord, called motor neurons, degenerate and die, resulting in muscle weakness and paralysis. Each year, approximately one in 6,000 to 10,000 infants is born with SMA and, tragically, the majority die before the age of two, often from respiratory failure. In fact, SMA is the leading genetic cause of death in infants and toddlers.

SMA is caused by the deficiency of a protein called survival of motor neuron (SMN), which is essential to the functioning of motor neurons. Consequently, considerable research is focused on increasing levels of SMN. With grants now totaling nearly $7 million, the SMA Foundation has supported research under the direction of Lee Rubin, PhD, HSCI Director of Translational Research, since he joined HSCI and established HSCI's Therapeutic Screening Center in 2006. The initial three-year grant, which was recently renewed for another two years, has enabled Rubin and his group to move the needle considerably closer to a potential cure for SMA. Using unique cell lines of SMA motor neurons from mice and also humans, Rubin and his team have identified pathways that regulate and boost levels of SMN. And in what is almost certainly a first, they have identified several compounds that not only increase SMN levels, but also prolong the survival of motor neurons, which is essential for any therapy to work.

"We've found ways to keep these cells happy and alive," says Rubin. "Our next step is to evaluate these compounds in mouse models of SMA, looking at motor neuron survival and neuromuscular function." Depending on the results, it is conceivable that a drug for SMA could enter clinical trials in the foreseeable future.

Through his work, Rubin and his group are building a deep base of knowledge about the similarities and differences between animal models and human cell models of disease that will help investigators move forward in SMA and other diseases more quickly. "Lee Rubin and his team are a core part of our strategy to drive the development of treatments for SMA. We are so grateful for their contributions, which extend beyond the screening lab to include new thinking about the disease, new collaborators in the field, and new ways that HSCI can be a part of the solution for SMA," says SMA Foundation President Loren Eng.

Rubin is very appreciative of the SMA Foundation's ongoing financial support and the organization's trust and confidence in his work, which enables him to focus on the critical task at hand—to make steady progress toward finding a cure for SMA.

"At HSCI, we have the specialized interdisciplinary expertise and cutting-edge technologies to make a difference in this disease, but we can't do it alone," says Rubin. "The support of the SMA Foundation has been and continues to be hugely important to finding a cure for this awful childhood disease."

Accelerating diabetes research: the Helmsley Charitable Trust

Another area in which disease foundations are playing a pivotal role is diabetes research. In 2009 the Leona M. and Harry B. Helmsley Charitable Trust launched an ambitious Type 1 Diabetes Program, the goal of which is to find a cure for this form of the disease, which typically afflicts children and young adults.

A unique facet of the program is the Type 1 Diabetes Research Consortium, a collaborative initiative that engages 11 institutions and 45 investigators through 28 grants totaling $21.8 million. The purpose of the consortium, which was initiated by Helmsley Charitable Trust Trustee David Panzirer, is to fund multi-institutional, cross-disciplinary projects that address research bottlenecks and accelerate or expand existing research programs, rather than duplicate existing efforts. HSCI Co-Director Douglas Melton, PhD, was selected to serve on the consortium's four-member scientific steering committee, along with scientists from the University of Florida, the University of California, and Columbia University.

Broadly speaking, the Type 1 Diabetes Research Consortium will investigate new strategies to restore the body's ability to control blood glucose levels, and to prevent the immune system from attacking existing or newly formed beta cells—the cells that produce insulin.

Specifically, grants have been awarded over a three-year period in four primary program areas: to identify how and why type 1 diabetes develops; to stop the destruction of beta cells; to create a renewable source of beta cells; and to reverse type 1 diabetes in patients. HSCI is the recipient of six grants totaling more than $5.7 million, four of which are focused on the second program area—stopping the destruction of beta cells. Creating a humanized mouse model

With Melton as project leader, this program brings together a cross-disciplinary team of scientists from within and beyond HSCI to create a "humanized" mouse model of type 1 diabetes. Current animal models of the disease lack features of the human immune system, so do not allow scientists to sufficiently understand the mechanisms that result in type 1 diabetes in humans.

Creating a humanized mouse model of type 1 diabetes and observing the triggering events that cause the disease will help researchers better understand how to arrest the immune system's assault on beta cells in vivo. "The better you can model human type 1 diabetes in a mouse, the closer you can come to understanding this disease and testing interventions," says HSCI faculty member Derrick Rossi, PhD, whose lab will contribute to generating the immune system in the humanized mouse model. Other scientists participating in this effort are Dale Greiner, PhD, University of Massachusetts Medical School; Leonard Shultz, PhD, Jackson Laboratory; Manfred Baetscher, PhD, HSCI's Genome Modification Facility; and Rene Maehr, PhD, Harvard's Department of Stem Cell and Regenerative Biology. Researchers from the University of California, San Francisco, and the University of Florida Foundation also are involved in this program.