Overview of Gene Therapy for SMA

Updated September 20, 2013

Click here for a Drug Discovery Compass on Gene Therapy.

Click here for a summary article from Genzyme on the status of SMA Gene Therapy.

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 cant 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.

What has FSMA's role been in the project?-In 2010, FSMA awarded $100,000 to Dr. Brian Kaspar at Nationwide Childrens Hospital for SMA gene therapy development. Please click here to read the announcement. -In 2011, Dr. Brian Kaspar published a paper in "Molecular Therapy" on systemic gene delivery in large species with FSMA funding. Please click here to read the annoucement. -In 2012, FSMA awarded Dr. Kaspar $750,00 in drug discovery funding to advance a CNS delivered gene therapy for SMA. Please click here to read the announcement. -In 2013, NINDS awarded a $3,752,462 to Dr. Kaspar in collaboration with FSMA to advance a CNS-directed gene therapy to IND. Please click here to read the announcement.

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, 271274 (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.

Go here to see the original:
Spinal Muscular Atrophy Gene Therapy Research

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