What is gene therapy? Gene Therapy is an approach to treating diseases by either modifying the expression of particular genes or by correcting abnormal genes. Gene therapy works by administration of DNA rather than a drug. Many different diseases are currently being investigated as candidates for gene therapy. These include cystic fibrosis, cardiovascular disease, AIDS, cancer and SMA.1
A gene that is inserted directly into a cell usually does not function. Instead, a carrier called a vector is genetically engineered to deliver the gene. Certain viruses are often used as vectors because they can deliver the new gene by infecting the cell. The viruses are modified so they can’t cause disease when used in people. Viruses, such as adenoviruses, introduce their DNA into the cell. The gene therapy vector can be given systemically by IV or injected directly into a specific tissue in the body, where it is taken up by individual cells, like motor neurons in the case of SMA.
How does gene therapy work in SMA? In the case of SMA, gene therapy could take several approaches. The most likely approach would be to replace the lost SMN1 gene in cells. A second approach could be to use small pieces of genetic material, called oligonucleotides, to improve the functioning of the back-up SMN2 gene. Please click here to read more about that approach. A third approach could be to use gene therapy to deliver neuroprotective proteins like growth factors to motor neurons to help keep them alive and well functioning.
The challenge with gene therapy for SMA is to find a way to deliver the genetic material to the spinal cord. A number of viruses are being studied for their ability to safely and effectively carrier the genetic material across the blood brain barrier, where they will be needed to treat a disease like SMA. In the past, these viruses could not cross the blood brain barrier. Recently one called AAV9 has been generated that reaches motor neurons very effectively. See figure below for details.
Figure 1. Gene therapy for mice with spinal muscular atrophy (SMA). SMA mice (null for the murine SMN gene and homozygous for variants of human SMN transgenes) are born with a normal motor neuron complement. However, the motor neurons undergo rapid attrition, likely a result of synaptic failure and denervation with attendant muscular atrophy. The mice become wasted and succumb at two weeks of age (left), analogous to an untreated mild human type I SMA. Injection of scAAV9-SMN into the facial vein of day-old SMA pups results in SMN expression in ~40% of motor neurons, normalization of synaptic electrophysiology and an extension of life span to >250 days, albeit at half the size of unaffected mice (right). Full results published in Foust, K.D. et al. Nat. Biotechnol. 28, 271–274 (2010). This result has been replicated by multiple labs worldwide, including at Genzyme Corporation, the lab of Dr. Martine Barkats, and the lab of Dr. Mimoun Azzouz. Figure reprinted by permission from Macmillan Publishers Ltd: Nature Biotechnology, Mackenzie A., Genetic therapy for spinal muscular atrophy. Volume 28: 236-7. Copyright 2010.
What will it take to make gene therapy work in humans? Currently there are no FDA approved gene therapy products in the United States. Gene therapy products are still being studied to assess their safety and efficacy in a wide variety of diseases. The main challenge in developing gene therapy approaches for all diseases is how to effectively and safely deliver the genetic material into a human.
What is the Current Development Status of Gene Therapy for SMA? After 2011 pre-pre IND meeting Dr. Brian Kaspar reported the following: "We had our first interaction with the Food and Drug Administration regarding our gene delivery program for Spinal Muscular Atrophy on Thursday, February 24th, 2011 in what is termed a pre-pre IND (Investigational New Drug Application). For this call, we presented pertinent information to the FDA regarding the status of our studies to date, which included pre-clinical efficacy and preliminary safety data. We were impressed with the thorough, thoughtful and expert review we received from the agency in which the FDA was positive regarding our program, providing guidance for moving our translational program forward. It is important to note that these discussions were informal and non-binding, but certainly provided positive direction for us to move towards human studies. Based on our conference call and review, we are planning to perform some further dosing and safety studies that will help guide the studies that will be required for our formal application. This was an important step in our program and we are excited to continue to advance the gene delivery program forward to the clinic."
After a 2012 RAC committee meeting: In December 2012, the Kaspar team at Nationwide Children's Hospital presented their program to the NIH Recombinant Advisory Committee (RAC). The NIH's RAC approved an infant trial for systemic AAV9-SMN Gene Therapy for SMA. FDA approval, which is required to begin any clinical trial in the US, will be sought in 2013. In the coming months, the team will submit an IND to the FDA for final approval to begin human clinical trials. FSMA funding is helping move this program into older and bigger patients with SMA. Click here to read more about the RAC approval.
In 2013, the FDA approved the IND filing to begin a Phase I trial in SMA infants: Following the submission of an Investigational New Drug application, the FDA has given its approval to physician-scientists at Nationwide Children’s Hospital to begin a Phase I clinical trial of a systemic AAV9-delivered human SMN gene. The clinical trial is expected to begin in the first half of 2014 and will be limited to Type I SMA patients, ages birth to 9 months. Click here to read about the trial.