FightSMA Gene Therapy Program: A History
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Background
FightSMA has been instrumental in developing a gene therapy strategy to cure spinal muscular atrophy (SMA), including oligonucleotides and gene replacement vectors. While SMA is clearly a devastating disease, the strides that SMA researchers have made in the gene therapy arena have provided incredible insights into a variety of genetic disorders, including other neurodegenerative disease (ALS/Lou Gehrig's disease, myotonic dystrophy, Huntington disease) and other diseases such as Duchenne muscular dystrophy.
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What is Gene Therapy?
For this purpose, we will focus upon the recently published results that directly impact SMA research: AAV gene therapy. AAV or Adeno-Associated-Virus is a small virus that has become widely adopted as a means to transfer genetic material into cells and animals, including humans. AAV can be thought of as the "vehicle" the delivers the therapeutic payload. The payload is a gene that would reduce or prevent disease development. Within the AAV vector, researchers can insert a variety of genes - in this case the Survival Motor Neuron (SMN) gene. It is important to note that the AAV used in all gene therapy work has been nearly completely "gutted" and does not contain a single viral gene. Therefore, this virus cannot replicate outside of the laboratory setting. Only the outside shell, or "capsid," remains as well as a small amount of genetic material used to package the SMN gene into the viral capsid. In SMA, the SMN gene is expressed at very low levels - so, a reasonable strategy would simply be to replace the SMN gene through AAV gene therapy. This is exactly what has been accomplished by Dr. Kaspar and colleagues. Additional publications (Passini et al., J Clin Invest, 2010; Valori et al., Sci Transl Med, 2010) have further bolstered the Kaspar findings in SMA models. Importantly, AAV9-SMN can enter motor neurons and restore high levels of SMN expression, thus preventing SMA development. Motor neurons function normally, muscles function normally, and the animals develop normally and live several hundred days compared to ~14 days for untreated animals. While it is always important to put this type of work in perspective, the results are extremely compelling and this work clearly puts AAV9-SMN on the front line in the fight against SMA.
AAV Opportunity for SMA
 Brian Kaspar, Ph. D. |
FightSMA, with a long-standing stake in SMA gene therapy, is now embarking on the next phase of gene therapy research. Several recent scientific reports have shown that Adeno-Associated-Virus (AAV)-9 can pass the blood brain barrier and enter motor neurons efficiently following intravenous administration - an important step to consider with regards to potential SMA treatments. To date, AAV-SMN gene therapy has proven to be the most dramatic therapeutic strategy in SMA animal models. An exciting report recently published in Nature Biotechnology by Dr. Brian Kaspar (Foust et al., Nature Biotechnology) details significant rescue of the SMA phenotype in a severe model of SMA. SMA mice that typically die before the end of two weeks live several hundred days and have no overt sign of disease development. This is truly exciting research, however, the next hurdle is to bring this work closer to a clinical trial for SMA patients - that is where this project steps in. This can only be done by a thorough analysis in larger animals and by performing toxicology analyses which will be the primary focus of this project. These are essential steps in the pre-clinical analysis of this relatively new gene therapy vector.
Dr. Kaspar participated in Nationwide Children's Hospital's monthly podcast about neuromuscular research and he spoke on a number of topics including:
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The Path Forward
FightSMA proposes to fund a program that encompasses several aspects of AAV9 pre-clinical work and the first step in the program is: safety and toxicity. This will be a multi-year endeavor and will be an ongoing point of emphasis for FightSMA. FightSMA is excited about partnering with Dr. Brian Kaspar of Nationwide Children's Hospital and The Ohio State University and collaborating scientists.
Important questions need to address
- What gene or "molecular payload" will be delivered?
- What vector will be used to deliver the gene?
- What route will the vector be administered?
With the dramatic results shown in the SMA model, it is clear that each of these questions is being addressed successfully in the SMA mice - but will there be broader application to other genetic diseases? To answer the first question, in all likelihood, the SMN gene will be very specific for SMA patients and will not have broad implications outside of the SMA world. However, the vector selection and the route of administration could have profound implications for other genetic diseases. In SMA, it is essential that motor neurons receive the vector - and motor neurons are within the central nervous system. Therefore, this type of work provides insight into a delivery paradigm for gene therapy vectors for other diseases affecting the central nervous system such as ALS, Alzheimer's Disease, and Parkinson's Disease.
Program Phases
Phase I: Toxicity in mice and large animals
The gene therapy "vector" AAV9 being used in the Kaspar results is quite new and there is almost nothing out there regarding safety/toxic data. This work is designed to build the foundation of safety and low toxicity. If the work is to move forward, the toxicity studies must be done. Much of the gene therapy work in the past was with AAV2, a vector closely related to AAV9. AAV2 has a very low toxic profile. It is encouraging that AAV9, a closely related virus to AAV2 does an infinitely better job of rescuing SMA. However, because it is different vector, the safety studies must be done. Toxicity in mice, step 1, and toxicity in large animals (monkeys), step 2, must be checked off in order for pre-clinical progress to be made for the AAV9 vector. The subsequent steps are more focused upon delivery, scaling up and efficacy.
Budget: $250,000
Phase II: Delivery and Efficacy
Delivery: It is hoped that the SMA large animal model will be in place towards the end of this study. And, at that time, a viable "large animal model" could be used to determine whether the SMA phenotype can be rescued in a large animal more comparable to humans. All of the other large animal testing will be done with healthy animals, because, a larger model doesn't not exist at this moment. This larger animal model is under development.
Efficacy: Efficacy can only be tested when there is actually a disease to cure (SMA mice or SMA pig). As contrasted with safety studies which are done in otherwise healthy animals.
Budget for Delivery and Efficacy: $500,000 - $800,000 over two to three years
Phase III: Scaling Up
Vector production for animals other than mice is one of the great barriers for gene therapy. It is a tremendous production to make enough virus to test larger animals. The size and development of the animal also impacts delivery of the vector. For example, in mice AAV9 efficiently enters motor neurons from an intravenous injection. Does this actually happen in a larger animal where the scale is completely different? It rarely translates directly from mice to larger animal models. How much virus is needed? At what age does the blood-brain-barrier block AAV9 from entering? Indeed, mouse development and primate development are very hard to translate.
Budget : $800,000+ per year, over two years.
The FightSMA mission and strategy is to provide seed funding and with those funds, allow scientists to prove principle. The National Institutes of Health offer this strong endorsement of translational research:
To improve human health, scientific discoveries must be translated into practical applications. Such discoveries typically begin at "the bench" with basic research - in which scientists study disease at a molecular or cellular level - then progress to the clinical level, or the patient's "bedside."
Scientists are increasingly aware that this bench-to-bedside approach to translational research is really a two-way street. Basic scientists provide clinicians with new tools for use in patients and for assessment of their impact, and clinical researchers make novel observations about the nature and progression of disease that often stimulate basic investigations.
Translational research has proven to be a powerful process that drives the clinical research engine. However, a stronger research infrastructure could strengthen and accelerate this critical part of the clinical research enterprise.
Terminology
Capsid - outside shell of a virus
Oligonucleotides - short stretches of nucleic acid such as DNA or RNA, however, newer chemistries have been developed that are incorporated into synthetic oligonucleotides. These modifications are generally designed to improve stability and/or cellular uptake of the oligonucleotides. Oligos can be used to inhibit expression of specific genes, or in the case of SMA, alter the RNA splicing of SMN2 exon 7 - leading to more full-length SMN
Toxicity - in therapeutic development, is critical because the introduction of any foreign compound/viral vector has the potential to cause the body to react in significant, and potentially damaging, ways. It is generally assumed that every therapeutic - even those that are incredibly effective and safe - can be toxic at high doses. Therefore, the challenge in early toxicology studies is to try to determine the balance between a toxic dose and an effective dose.
Vector - a vehicle, such as a virus, used to transfer foreign genetic material into another cell
The above was prepared by FightSMA's Science Director, Chris Lorson, Ph.D., Associate Professor, University of Missouri.