Laboratory of Molecular Design
Huntingtin mRNA PET Imaging to Quantify Therapeutic Efficacy

      Clinical trials of genetic therapy to knock down mutant huntingtin (HTT) mRNA in Huntington’s disease (HD) are imminent. We have pioneered mRNA positron emission tomographic (PET) imaging of CCND1, MYCC, and KRAS2 oncogene mRNAs in cancer cells and in mouse tumor models. We hypothesize that external PET imaging of HTT mRNAs in brain cells will enable quantification of therapeutic efficacy. Specific Aim 1: We will design a positron-emitting HTT mRNA hybridization agent, and a PNA sequence mismatch control. The agent will include a cell-penetrating peptide derived from HIV Tat to maximize uptake. We will quantify accumulation of radiolabeled HTT mRNA imaging agents in HTT-expressing cells in culture, vs. mismatch controls, and vs. control cells that do not express HTT mRNA. We will also prepare fluorescent agents to reveal intracellular trafficking. Specific Aim 2: We will design a second HTT mRNA hybridization agent, which includes a cell-penetrating peptide derived from the Antennapedia homeodomain third helix. We will determine HTT-expressing cell accumulation and trafficking as in Aim 1, vs. mismatch control, and vs. HTT-negative control cells. Results consistent with our hypothesis will lead to immediate and longitudinal quantitative PET imaging of HTT mRNA in therapeutic animal models.

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