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  • Addiction, Drugs
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    728—Disorders of the Nervous System: Gene Therapy

    Wednesday, November 13, 2013, 8:00 am - 12:00 noon

    728.09: Preclinical studies supporting a gene therapy trial for Giant Axonal Neuropathy

    Location: Halls B-H

    1Gene Therapy Ctr., 2Departments of Radiology & Pathology and Lab. Med., 4Psychiatry and Orthodontics, 3Univ. of North Carolina, Chapel Hill, NC

    Abstract Body: Giant Axonal Neuropathy (GAN, OMIM #256850) is a rare, pediatric, neurodegenerative disease characterized by enlarged axons with disordered microtubules and intermediate filaments (IFs). The disease is fatal by the third decade due to severe neuronal dysfunction and axonal degeneration within the peripheral and central nervous system (CNS). GAN is characterized by homozygous mutations in the GAN gene, which encodes the protein gigaxonin. Pathologic hallmarks consist of disorganization and dense accumulation of gigaxonin-regulated IFs.
    In order to treat GAN, we devised a gene transfer approach to deliver adeno-associated virus (AAV) vectors carrying the gigaxonin gene to the CNS, by injection into the cerebrospinal fluid by lumbar puncture. Proof-of-principle experiments demonstrated the ability of AAV/GAN vectors to rapidly resolve IF aggregates in GAN KO mice and cultured fibroblasts of GAN patients. Widespread CNS biodistribution of the AAV9 vectors following intrathecal administration was validated in mice and non-human primates. Efficacy following gene transfer was documented in GAN KO mice receiving an intrathecal injection of the AAV9/GAN vector at 18 months, after onset of symptoms, by a significant improvement in motor function and rescue of sciatic nerve ultrastructure at 6 months post-injection.
    A preIND meeting with the US FDA was held to receive guidance on a human gene transfer trial for GAN. Subsequent toxicology and biodistribution studies in mice and non-human primates strongly support the safety of this approach, and a Phase I Safety trial is expected to begin within the year.
    Ongoing studies are aimed at examining possible biomarkers to better quantify the therapeutic response that may be observed in human subjects, towards facilitating future transition to a Phase II/III trial. One valuable resource is magnetic resonance imagining (MRI). Conventional MR sequences have shown widespread white matter abnormalities in GAN patients and advanced MR techniques such as Diffusion Weighted Imaging (DWI) and Diffusion Tensor Imaging (DTI) hold promise in quantifying and monitoring CNS involvement in GAN. Our pilot studies in 18-month old KO mice showed significantly enlarged volumes for spinal cord white matter and for total brain volume, which can be localized to specific structures such as the corpus collosum. Mean, axial, and radial diffusivity was significantly reduced in localized brain regions, whereas fractional anisotropy was increased. Reduced diffusion values typically represent compromised white matter microstructure within a specific region and potential alterations in neuroconnectivity between different sites.

    Lay Language Summary:: Researchers at the University of North Carolina Gene Therapy Center have developed a gene therapy approach to treat a rare and fatal childhood disease called Giant Axonal Neuropathy (GAN). Children born with GAN have had no treatment options, but this gene therapy approach offers a potentially lifelong benefit from a single treatment. Importantly, the approach taken to treat GAN is readily transferable to similar inherited diseases like spinal muscular atrophy and Friedrich’s ataxia, and it paves the way for new treatments for a variety of other diseases such as amyotrophic lateral sclerosis and Alzheimer’s disease.
    In collaboration with Dr. Carsten Bonnemann’s group at the NIH Clinical Center, a clinical trial to test this approach in humans with GAN is planned to start within the year. This approach was approved by the NIH Recombinant DNA Advisory Committee in June of 2013, following favorable comments and broad support from patient advocates. Our approach will be the 1st every clinical trial for a GAN therapy, and currently offers the only hope to these patients.
    Mice with GAN were injected with a modified adeno-associated virus (AAV) that was engineered to carry the missing gigaxonin gene rather than any viral DNA. In this case, the AAV serves as a molecular delivery vehicle, or vector, to carry the therapeutic gene into the patient’s cells. This corrects the patient’s defective DNA, providing a permanent fix after a single treatment. The mice showed improvement in their motor function 6 months after treatment, lessening the severity of the disease. The injection was via a spinal tap, a simple outpatient procedure.
    Preclinical work is being carried out at the UNC Gene Therapy Center to take an identical approach in treating other inherited neurological disorders including Krabbe disease, Batten disease, Tay-Sach’s disease, apartylglucosaminuria, and Rett syndrome. The same AAV vector and injection approach are utilized, but a different gene is delivered. Work is also being done to create better AAV vectors, improving the overall efficiency of the approach.
    GAN is a progressive and fatal loss of motor and sensory function. It is caused by an inborn defect in a single gene called gigaxonin. Children with GAN decline to the point where they require a wheelchair before their teenage years. By the late teenage years they often require assisted breathing, and lose control of their arms. GAN is typically fatal in the 20s. A small non-profit foundation called Hannah’s Hope Fund (www.hannahshopefund.org) was started in 2008 with the mission of finding a treatment for GAN.
    This effort is the culmination of 5 years of research conducted at the UNC Gene Therapy Center and funded entirely by Hannah’s Hope Fund. The molecular benefits of gigaxonin gene transfer were proven in cultured patient cells and in mice. Improvement in disease symptoms and preservation of peripheral nerves was further demonstrated in mice with GAN following treatment. Advanced imaging techniques (MRI) and are being utilized to further document the treatment effects in mice, and these can provide a means to non-invasively monitor treatment effects in humans. The approach to transfer the gene using AAV vectors was validated in mice, pigs, and monkeys, providing confidence that this treatment can translate to humans.