Nationwide Children’s Hospital, in Columbus, OH, cares for children from around the world. Its research institute is among the top 10 free-standing children’s hospitals in terms of National Institutes of Health funding. Its Center for Gene Therapy develops treatments for a variety of childhood disorders, particularly neuromuscular and neurodegenerative diseases, and collaborates with pharmaceutical companies to move potential therapies into clinical trials. What is the state of the art of gene therapy today? 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 many 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. What success have you had in developing therapies? The most striking published result so far has 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 Brian Kaspar in his lab at Nationwide Children’s, Jerry Mendell’s team treated 15 patients with systemic delivery of an AAV9 vector carrying the SMN gene. They showed it was safe, but more strikingly, all of the patients were alive or without mechanical ventilation at age 20 months, as compared to only the 8% expected based upon natural history studies. This is really quite a dramatic change in the clinical course, and has the potential to change treatment of the disease around the world. What other diseases are you tackling? We have trials under way for Duchenne muscular dystrophy, which affects about 1 in 5200 boys. These trials include gene transfer of micro-dystrophin, miniaturized to fit into an AAV capsid, as well as a surrogate gene (GALGT2) that can in some ways substitute for the missing protein. We have trials under way or planned for some forms of limb-girdle muscular dystrophy and Charcot-Marie-Tooth disease, and ongoing preclinical projects addressing facioscapulohumeral muscular dystrophy, myotonic dystrophy type 1, and a variety of other neuromuscular disorders. In addition, we have trials under way for other diseases that primarily affect the central nervous system, such as Sanfilippo syndrome (or mucopolysaccharidosis type 3) and Batten disease. Why do you emphasize childhood neuromuscular diseases? Most importantly, many childhood neuromuscular diseases are absolutely devastating disorders for which no other therapy is available. I have studied these diseases for 25 years, and my colleague Jerry Mendell has worked on them for more than 50 years, so we know this patient population well. We have viruses that are taken up by skeletal muscle quite well, and we can biopsy muscle to directly evaluate how our viral payloads are expressed, which is very helpful. We also have an excellent clinical research team that continues to develop and validate appropriate functional outcomes in these diseases, which is necessary for good clinical trials. Could you move into treating other diseases? The lessons learned from preclinical and clinical studies with vectors for neuromuscular diseases are applicable to many other diseases. We don’t expect these approaches will work only for neuromuscular diseases, but that’s where our areas of interest have historically been, and these studies have allowed us to demonstrate proof of concept in human safety and efficacy. As I mentioned earlier, we have programs directed toward the central nervous system as well. We’ve gained a lot of experience in navigating the regulatory process. We have an in-house regulatory group, and it’s one of the reasons that we’ve submitted more than 15 active gene therapy Investigational New Drug applications. We will have multiple new INDs coming out within the next year. How does gene therapy fit with pediatric medicine? Many pediatric disorders are devastating or lethal, which makes the argument for starting with these most severe diseases. One advantage in pediatric medicine is that one of the great challenges of gene therapy is manufacturing sufficient quantities of any viral vector. Since many of these therapies dose by weight, using a given number of virus particles per kilogram, we can test them more readily in pediatric diseases, and can design trials that involve more patients. Are you optimistic that gene therapy will reach the clinic? I am very optimistic. One sign that it’s moving toward practice is the number of biopharmaceutical companies that are now developing gene therapies. Some of these are companies that we have partnered with, but regardless of whether we consider products licensed from Nationwide Children’s or elsewhere, the enthusiastic and growing engagement of biopharma partners signals great confidence in the field.
What is the state of the art of gene therapy today?
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 many 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.
What success have you had in developing therapies?
The most striking published result so far has 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 Brian Kaspar in his lab at Nationwide Children’s, Jerry Mendell’s team treated 15 patients with systemic delivery of an AAV9 vector carrying the SMN gene. They showed it was safe, but more strikingly, all of the patients were alive or without mechanical ventilation at age 20 months, as compared to only the 8% expected based upon natural history studies. This is really quite a dramatic change in the clinical course, and has the potential to change treatment of the disease around the world.
What other diseases are you tackling?
We have trials under way for Duchenne muscular dystrophy, which affects about 1 in 5200 boys. These trials include gene transfer of micro-dystrophin, miniaturized to fit into an AAV capsid, as well as a surrogate gene (GALGT2) that can in some ways substitute for the missing protein. We have trials under way or planned for some forms of limb-girdle muscular dystrophy and Charcot-Marie-Tooth disease, and ongoing preclinical projects addressing facioscapulohumeral muscular dystrophy, myotonic dystrophy type 1, and a variety of other neuromuscular disorders. In addition, we have trials under way for other diseases that primarily affect the central nervous system, such as Sanfilippo syndrome (or mucopolysaccharidosis type 3) and Batten disease.
Why do you emphasize childhood neuromuscular diseases?
Most importantly, many childhood neuromuscular diseases are absolutely devastating disorders for which no other therapy is available. I have studied these diseases for 25 years, and my colleague Jerry Mendell has worked on them for more than 50 years, so we know this patient population well. We have viruses that are taken up by skeletal muscle quite well, and we can biopsy muscle to directly evaluate how our viral payloads are expressed, which is very helpful. We also have an excellent clinical research team that continues to develop and validate appropriate functional outcomes in these diseases, which is necessary for good clinical trials.
Could you move into treating other diseases?
The lessons learned from preclinical and clinical studies with vectors for neuromuscular diseases are applicable to many other diseases. We don’t expect these approaches will work only for neuromuscular diseases, but that’s where our areas of interest have historically been, and these studies have allowed us to demonstrate proof of concept in human safety and efficacy. As I mentioned earlier, we have programs directed toward the central nervous system as well. We’ve gained a lot of experience in navigating the regulatory process. We have an in-house regulatory group, and it’s one of the reasons that we’ve submitted more than 15 active gene therapy Investigational New Drug applications. We will have multiple new INDs coming out within the next year.
How does gene therapy fit with pediatric medicine?
Many pediatric disorders are devastating or lethal, which makes the argument for starting with these most severe diseases. One advantage in pediatric medicine is that one of the great challenges of gene therapy is manufacturing sufficient quantities of any viral vector. Since many of these therapies dose by weight, using a given number of virus particles per kilogram, we can test them more readily in pediatric diseases, and can design trials that involve more patients.
Are you optimistic that gene therapy will reach the clinic?
I am very optimistic. One sign that it’s moving toward practice is the number of biopharmaceutical companies that are now developing gene therapies. Some of these are companies that we have partnered with, but regardless of whether we consider products licensed from Nationwide Children’s or elsewhere, the enthusiastic and growing engagement of biopharma partners signals great confidence in the field.
