Many childhood diseases have either a genetic basis or predisposition. Some are entirely the result of a change in one gene. Many more are the result of the interaction between a person's genetic makeup and other factors, like environment and lifestyle.
In my institution, Nationwide Children's Hospital, we are using the science of genomics to investigate the genetic underpinnings of disease, and we are studying gene therapies as potential ways to help treat them.
In 2016, we recruited renowned genomics experts Richard Wilson, PhD, and Elaine Mardis, PhD, and created the Institute for Genomic Medicine. This team is accelerating the discovery of disease-causing genes and using a patient's genomic data to guide treatment.
As part of our strategic plan, we are working to bridge the gap between basic research and clinical genomics. The Institute for Genomic Medicine's clinical and genomic services laboratories, computational genomics, technology development group and translational research programs fall under the same umbrella, collaborating to focus on more than just DNA.
The Institute's recently developed cancer protocol is aimed at moving genomics into direct patient care. It is designed to elucidate the genomics of a patient's tumor and to make some tests available to patients prior to clinical availability.
The cancer protocol starts with patient nominations from our oncologists. In most cases, the patients have tumors that did not respond to prior rounds of therapy or have recurred. Selected patients are invited to have a full genomic analysis performed. Institute faculty then study tumor and normal DNA and compare the sequences of all known genes. They look for cancer susceptibility genes by testing the normal cells' DNA, and examining both the cancer DNA and RNA for clues to what is driving a patient's cancer and might help guide therapy.
This is what physician-scientists around the world mean when they talk about a future of “precision medicine.” If genomics is the science of investigating the genetic code, gene therapy is a promising method to address those disease-causing findings.
After more than 20 years of research into gene transfer, it is finally reaching the clinic in a meaningful way. Part of this is based on the increasingly successful development of the viral vector systems we now use, adeno-associated viruses (AAVs), which have become the workhorses for gene therapy. After years of preclinical research with AAV vectors, gene therapies for many single-gene disorders are now in clinical trials. Some have already shown extraordinary promise for changing the disease course for devastating childhood illnesses.
Some of the most striking published results so far have been in gene transfer of the SMN1 gene into patients with spinal muscular atrophy type 1, where the first human trial showed a dramatic improvement in outcomes. This devastating disorder affects the motor neurons, and typically causes death or the need for mechanical ventilation by the age of two years. Using a vector developed by Dr. Brian Kaspar in his lab at Nationwide Children's, Dr. Jerry Mendell, a renowned neurologist and scientist at Nationwide Children's, and his team treated 15 patients with systemic delivery of an AAV9 vector carrying the SMN gene. They showed it was safe, but more remarkably, all of the patients were alive or without mechanical ventilation at age 20 months, as compared to only the 8 percent expected based upon natural history studies. This is a dramatic change in the clinical course, and has the potential to change treatment of the disease around the world. This study was voted by the readers of Science as a 2017 Breakthrough of the Year.
Nationwide Children's has a vision of continued genetic discovery and therapeutic development. We have submitted more than 15 active gene therapy Investigational New Drug applications, with more in the near future. Our investment in genomics makes genetic discoveries possible; our commitment to gene therapy drives innovative therapeutic development. We are focused on the future of child health, and working to make novel therapies a reality today.