Department of Paediatrics
Murdoch Childrens Research Institute
Developing bone marrow transplant and lentiviral vectors to treat Friedreich ataxia
Sze Hwee Ong1,2, Dong C. Zhang2,3, Chou H. Sim1,2, Matthew Burton4, Dean Phelan1,2, Sarah E.M. Stephenson1,2, Gabrielle R. Wilson1,2, Donald F. Newgreen2,3, Anthony J. Hannan5, Paul J. Lockhart1,2, Martin B. Delatycki1,2,6, Marguerite V. Evans-Galea1,2.
1Bruce Lefroy Centre, Murdoch Childrens Research Institute, Melbourne, Australia; 2Department of Paediatrics, The University of Melbourne, Melbourne, Australia; 3Embryology, Murdoch Childrens Research Institute, Melbourne, Australia; 4Scientific Services, Murdoch Childrens Research Institute, Melbourne, Australia; 5Neural Plasticity, Florey Institute of Neuroscience and Mental Health, Melbourne, Australia; 6Clinical Genetics, Austin Health, Melbourne, Australia
Neurodegenerative disorders, such as Friedreich ataxia (FRDA), are debilitating and decrease the quality of life of affected patients. FRDA is characterised by progressive gait and limb ataxia and cardiomyopathy. Affected individuals experience ongoing loss of motor coordination and become wheelchair-dependent within 15 years of disease onset. Life expectancy is approximately 40-50 years with heart complications the primary cause of death. Despite the availability of symptomatic treatments to manage disease symptoms, none can cure FRDA nor slow the neurodegeneration inherent to this disease. Due to such limited treatment options, it is crucial to develop new and more effective treatments to slow disease progression and improve the quality of life for FRDA patients. FRDA is caused by a homozygous trinucleotide (GAA) repeat expansion within intron 1 of FXN which encodes the frataxin protein. This expansion does not alter the frataxin protein but reduces its levels. It is anticipated that increasing frataxin will be therapeutically beneficial to FRDA patients. Our research aims to introduce frataxin into cells using cell and gene therapy to develop a potential treatment for FRDA. A significant advantage of cell and gene therapy in FRDA is that introduction of frataxin will not illicit an immune response since patients already express frataxin at very low levels. We are examining if transplanting a FRDA mouse model with wild-type bone marrow increases frataxin and alleviates the neurological phenotype in corrected mice. FRDA mice develop slight coordination impairment and locomotor defects at approximately six months of age. Reconstitution of the haematopoietic system with GFP-positive donor bone marrow cells in corrected recipient mice demonstrated successful engraftment following transplant. We have also observed engraftment of GFP-positive cells in the dorsal root ganglia (DRG) and spinal cord, both major sites of neuropathology in FRDA, of corrected mice post-transplant – indicative of low-level chimerism. In immunofluorescence studies, we observe increased neuronal marking in the DRG of corrected mice post-transplant, in particular proprioceptive neurons which are known to be more affected in FRDA patients. Frataxin protein increases in a number of tissues in corrected mice post-transplant. Corrected mice also displayed significant improvement in motor coordination post-transplant. Toward autologous gene therapy via bone marrow transplant, we have developed an insulated lentiviral vector that over-expresses frataxin and we are currently designing new vectors using cellular promoters. These data together indicate the corrective potential of bone marrow transplant to treat FRDA in vivo and provide an avenue for the delivery of therapeutic viral vectors for gene therapy.
15:30 - 17:00
|Stem Cells Bioengineering, and Preclinical Work||Developing bone marrow transplant and lentiviral vectors to treat Friedreich ataxia||Room 111-112|