By: Meredith A. Achey, BM


COMPOUND: Artificial micro RNA targeting human huntingtin, carried by an adeno-associated virus 5 (AAV5) vector (AAV5-miHTT)

MECHANISM OF ACTION: Micro RNAs (miRNAs) target messenger RNA (mRNA) transcripts and lead to silencing of the gene by suppressing translation. uniQure’s design also incorporates DNA promoters to enhance transcription of the miRNAs in target tissues, and the AAV5 vector is especially effective in targeting liver and neuronal tissues.1 AMT-130 was selected in preclinical studies both for efficacy in lowering mutant huntingtin production and for minimizing off-target effects.2

Figure: HTT silencing gene therapy

(1) Adeno-associated viral vector silencing human HTT gene (AAV5-miHTT) binds to neuron cell-surface receptors and is internalized. (2) The viral vector is transported into the nucleus and then degrades, uncoating the miHTT transgene. (3) The miHTT transgene is expressed and processed by the endogenous RNA interference machinery. (4) The hairpin structured precursor of miHTT is transported to the cytoplasm and further processed to the final mature miHTT. (5) The mature miHTT binds HTT messenger RNA, and the RNA duplex is recognized by RNA-induced silencing complexes. (6) HTT messenger RNA is cleaved, resulting in lowering of huntingtin protein expression. Image and caption courtesy of uniQure.

1 Maczuga P, Lubelski J, van Logtenstein R, et al. Embedding siRNA sequences targeting Apolipoprotein B100 in shRNA and miRNA scaffolds results in differential processing and in vivo efficacy. Mol Ther. 2013;21(1):217-227.

2 Miniarikova J, Zanella I, Huseinovic A, et al. Design, Characterization, and Lead Selection of Therapeutic miRNAs Targeting Huntingtin for Development of Gene Therapy for Huntington’s Disease. Mol Ther Nucleic acids. 2016;5(3):e297.