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Non-invasive and allele-specific silencing therapy for Polyglutamine disorders: the case of Machado-Joseph disease/Spinocerebellar ataxia type 3

Rui J. Nobre1, 2, 3*, Joana Saraiva1, Susana Paixão1, Clelia Fusco1, Magda Santana1, 2, Catarina O. Miranda1, 2, Lorena Petrella4, Jose Sereno4, Joao Castelhano4, Miguel Castelo-Branco4, Miguel Sena-Esteves5 and Luis Pereira De ALmeida1, 3, 6
  • 1 Centre for Neuroscience and Cell Biology, University of Coimbra, Portugal
  • 2 Institute for Interdisciplinary Research, University of Coimbra, Portugal
  • 3 University of Coimbra, Portugal
  • 4 Institute of Nuclear Sciences Applied to Health, University of Coimbra, Portugal
  • 5 Gene Therapy Center, University of Massachusetts Medical School, United States
  • 6 Faculty of Pharmacy, University of Coimbra, Portugal

Spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease is the most common dominantly-inherited ataxia. Although there is no cure, our group and others have been shown that RNA interference holds great promise for its treatment. With the aim of translation to clinics, in this project we developed an adeno-associated viral vector serotype 9 (AAV9)-based system that enables an allele-specific silencing of mutant ataxin-3. For that, specific gene silencing RNAs, whose anti-sense sequences were complementary to SNPs that are in linkage disequilibrium with the disease-causing expansion were designed and tested in modified neuronal cell lines. An AAV9 vector encoding the most effective silencing RNA (AAV9-mirATAX3) was then generated and validated in a lentiviral-based model of SCA3 upon intracranial injection. Finally, severely-impaired transgenic mice were intravenously-injected at postnatal day one (PN1), followed by behavioral tests at three different time points, underwent Magnetic resonance imaging/spectroscopy (MRI/MRS) at PN75 and were sacrificed at PN95. The silencing potential of the mirATX3 sequence demonstrated superior specificity in vitro compared to the silencing sequences previously reported. AAV9-mirATAX3’s treatment reduced the number of protein aggregates and cerebellar neuropathology in both animal models and led to significant improvements in behavioral tests. Moreover, MRI/MRS data indicated that mirATXN3 treatment ameliorates the levels of a specific set of neurometabolites, which can be used as therapeutic biomarkers. This study provides compelling evidence that AAV9-mirATAX3 is able to silence mutant ataxin-3 in different disease models, upon intracranial or intravenous administration. This may have a significant impact on the treatment of SCA3, as well as other Polyglutamine diseases.

Acknowledgements

Regional Operational Program Center 2020, COMPETE 2020 and FCT (projects CENTRO-01-0145-FEDER-000008, ViraVector CENTRO-01-0145-FEDER-022095, SpreadSilencing POCI-01-0145-FEDER-029716, POCI-01-0145-FEDER-007440, CortaCAGs (POCI-01-0145-FEDER-016719), PTDC/BBB-NAN/0932/2014, EXPL/NMC/0331/2012 and SFRH/BPD/66705/2009); by NAF and by the AFM-Téléthon no. 21163.

Keywords: Polyglutamine disorders, Machado-Joseph Disease, Gene Therapy, RNA interference (gene silencing), Adeno-associated viral vector serotype 9

Conference: XVI Meeting of the Portuguese Society for Neuroscience (SPN2019), Lisboa, Portugal, 30 May - 1 Jun, 2019.

Presentation Type: Poster presentation

Topic: Neurodegeneration / Physiological Aging Brain

Citation: Nobre RJ, Saraiva J, Paixão S, Fusco C, Santana M, Miranda CO, Petrella L, Sereno J, Castelhano J, Castelo-Branco M, Sena-Esteves M and Pereira De ALmeida L (2019). Non-invasive and allele-specific silencing therapy for Polyglutamine disorders: the case of Machado-Joseph disease/Spinocerebellar ataxia type 3. Front. Cell. Neurosci. Conference Abstract: XVI Meeting of the Portuguese Society for Neuroscience (SPN2019). doi: 10.3389/conf.fncel.2019.01.00007

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Received: 16 Apr 2019; Published Online: 27 Sep 2019.

* Correspondence: Dr. Rui J Nobre, Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Coimbra, 3004-504, Portugal, rui.jorge.nobre@gmail.com