b107a004e7f2ecfd1114116ce7a97486_f103GAN Gene Delivery

(Text in italics was added by web page admin.)

Dr. Steven Gray, from the gene therapy center at UNC at Chapel Hill, is leading Hannah’s Hope Fund’s gene delivery project. To date, no human has ever received a therapeutic gene to the spinal cord. The challenge is two-fold:

  1. Get the viral vector (a tool commonly used by molecular biologists to deliver genetic material into cells) across the Blood Brain Barrier (BBB), which is an extra protective layer surrounding the cells in the central nervous system (CNS);
  2. Localize delivery with traditional lumbar puncture administration to the cord resulting in only a few cells treated. Because the GAN gene encodes an intracellular protein, not a secreted enzyme, it’s critical to treat as many cells as possible.

With gene delivery, scientists use a benign viral vector to transport healthy copies of genes to targeted cells. The virus infects the cells with a healthy copy of the gene that will, in theory, have life-long expression of a protein missing in the cells of subjects with GAN. To date, longevity studies conducted at other academic institutions reveal AAV viral vector will express out for at least 12 years. (AAV: Adeno-associated virus is a small virus that is not currently known to cause disease and consequently the virus causes a very mild immune response. AAV can infect both dividing and non-dividing cells and may incorporate its genome into that of the host cell. These features make AAV a very attractive candidate for creating viral vectors for gene therapy.)

Clinical trials for a number of disorders of the brain have been long underway because viral vectors tend to spread in the cerebral spinal fluid along axonal pathways and multiple injections can be performed to achieve greater spread. With our novel route of administration of AAV serotype 9, (serotype: distinct variations within a subspecies of bacteria or viruses) subjects with GAN will likely be the first disease community to receive a therapeutic gene to the spinal cord.

Studies Demonstrate Hopeful Results

The first study HHF funded was to compare gene therapy viral vector serotypes and try different routes of administration to see if a new viral serotype would cross the BBB and give broad distribution throughout the cerebral spinal fluid that bathes the spinal cord. We discovered AAV serotype 9 is crossing the BBB.

We then funded a biodistribution study (the distribution of compounds within a biological system) to see if we could increase spread of the viral vector throughout the cerebral spinal fluid. We learned AAV9 is transducing (the transfer of genetic material from one microorganism to another by a viral agent) 80% of nerve cells in the spinal cord with a healthy copy of the gene when administered via a novel route of administration. We discovered that threading a catheter all the way up the spinal canal and releasing the viral vector at 3 loci allowed from broad distribution of the virus. These results are far better than expected. Most geneticists feel if you can treat 10 to 15% of cells with a therapeutic gene, disease course can be dramatically altered. This biodistribution study conducted in collaboration with Dr. Nicholas Boulis, Emory University, indicates GAN gene delivery will very likely have significant impact on this disease and may completely halt disease progression. It is anticipated that function may be restored to any nerve cell not yet dead.

Scientific UpdateAugust 2011