GM1 gangliosidosis is a neurodegenerative lysosomal storage disease caused by an enzyme deficiency in b- galactosidase that results in buildup of GM1 ganglioside throughout the nervous system. Though first described in 1881, the gangliosidoses remain incurable today and, until the last 5 years, little hope for a successful treatment has been forthcoming. Truly remarkable results of adeno-associated viral (AAV) gene therapy in the feline gangliosidosis models support the initiation of human clinical trials. However, a barrier to the accurate evaluation of therapeutic benefit in clinical trial patients is he lack of an objective biomarker with which to track disease progression. The goal of the following specific aims is to use permutations of magnetic resonance imaging (MRI) to effectively evaluate disease progression (or retention of function) in gangliosidosis cats with or without AAV treatment.
Aim. 1 Obtain serial high resolution images of the feline GM1 gangliosidosis brain using a 7 Tesla (T) MRI.
Aim2. Evaluate brain biochemistry in gangliosidosis with MR spectroscopy (MRS).
Aim 3. Identify metabolite profiles in the gangliosidosis brain using high resolution nuclear magnetic resonance (NMR) spectroscopy. Training of the applicant will be conducted through MRI short courses offered by the sponsoring and external institutions, nuclear magnetic resonance training through the sponsor institution, Responsible Conduct of Research modules and seminars, and daily interactions with the sponsor, co-sponsor and key personnel. Anatomical images in the current proposal will be acquired with the 7T scanner and quantitative measurements will be taken of cortical and subcortical targets such as the thalamus, caudate nucleus and brain stem. Using MRS, peak resonances from metabolites such as guanidinoacetate or Gal-b(1- 6)Gal-b(1-4)GlcNAc, oligosaccharides that have been reported in GM1 gangliosidosis brain, will be measured in each cat at the level of thalamus, frontal cortex, occipital lobe, temporal lobe and cerebellum. High resolution NMR spectroscopy will allow for quantitative analysis of brain metabolites described above and any novel metabolites encountered during the completion of this study. Through the use of magnetic resonance-based technology, this project will more thoroughly characterize gangliosidosis disease progression in untreated cats and evaluate therapeutic benefit in cats treated by AAV gene therapy.
Feline gangliosidosis is a model of human gangliosidosis, a devastating and incurable disorder that is fatal in most instances by 5 years of age, after a prolonged vegetative state in which children are non-responsive and nourished by gastric feeding tube. Gene therapy studies using the feline gangliosidosis model have generated outstanding results that support the initiation of human clinical trials, but an objective way to track disease progression in people is lacking. This study will evaluate disease progression in treated and untreated animals with noninvasive imaging methods that can be applied to people.
| Gray-Edwards, Heather L; Jiang, Xuntian; Randle, Ashley N et al. (2017) Lipidomic Evaluation of Feline Neurologic Disease after AAV Gene Therapy. Mol Ther Methods Clin Dev 6:135-142 |
| Gray-Edwards, Heather L; Regier, Debra S; Shirley, Jamie L et al. (2017) Novel Biomarkers of Human GM1 Gangliosidosis Reflect the Clinical Efficacy of Gene Therapy in a Feline Model. Mol Ther 25:892-903 |
| McCurdy, Victoria J; Johnson, Aime K; Gray-Edwards, Heather L et al. (2014) Sustained normalization of neurological disease after intracranial gene therapy in a feline model. Sci Transl Med 6:231ra48 |
| Gray-Edwards, Heather L; Salibi, Nouha; Josephson, Eleanor M et al. (2014) High resolution MRI anatomy of the cat brain at 3 Tesla. J Neurosci Methods 227:10-7 |
