Objective: To assess the effects of intrastriatal AAV5-miHTT therapy on MRS signal and mutant huntingtin levels in the Q175FDN mouse model of HD.

Background: Huntingtin (HTT)-lowering therapies are currently in clinical testing for Huntington’s disease. The development of improved non-invasive translational efficacy measures will be crucial for the assessment of HTT-lowering therapies in HD patients.

Method: We explored the use of a non-invasive technique, magnetic resonance spectroscopy (MRS), as a potential in vivo measure of the effects of HTT lowering using an adeno-associated virus serotype 5, engineered microRNA vector targeting human HTT (AAV5-miHTT). Three-month-old homozygous Q175FDN HD mice were injected bilaterally into the striatum with formulation buffer (sham), low (5.2 X 109 gc/mouse) or high (1.3 X 1011 gc/mouse) doses of AAV5-miHTT. Wild-type (WT) mice injected with formulation buffer served as controls. T1-weighted structural MR imaging (MRI) and striatal MRS were performed 3 months after injection, and shortly afterwards the animals were sacrificed to collect brain tissue.

Results: Decreased total N-acetylaspartate (tNAA, neuronal integrity marker) and increased myo-inositol (mI, gliosis marker) levels were found in Q175FDN sham-treated mice with respect to WT controls, similarly to previous observations in the putamen of HD patients. These findings were reversed in the Q175FDN high-dose AAV5-miHTT treated mice with higher levels of tNAA and reduced levels of mI compared to sham-treated Q175FDN mice. Structural MRI showed reduced volumes in striatum, cortex, hippocampus and thalamus of Q175FDN mice versus WT controls, with partial reversal of hippocampal volume loss in the high-dose AAV5-miHTT treated mice. Dose-dependent changes in AAV5 vector DNA level, miHTT expression and HTT protein were observed in striatum and cortex. Correlations were shown between tNAA MRS levels and AAV5 vector DNA, miHTT and HTT protein levels in striatum and cortex, suggesting a direct relationship between our AAV5-miHTT therapy, HTT lowering and the striatal MRS signal.

Conclusion: Striatal MRS analysis suggests a restoration of neuronal function and partial reversal of gliosis after AAV5-miHTT treatment, strengthening the therapeutic potential of AAV5-miHTT in lowering HTT and reversing the neuropathology of HD, and supporting the use of MRS for HTT-lowering clinical trials in HD.

References: None

« Back to 2019 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/exploring-the-effects-of-intrastriatal-aav5-mihtt-therapy-on-mrs-signal-and-mutant-huntingtin-levels-in-the-q175fdn-mouse-model-of-hd/