By: Daniel Zielonka, MD, PhD
More than 20 years after the identification of the wildtype HTT gene and the mutated allele (mHTT) that causes HD, we still have no cure, although there are a few therapeutic options for HD symptoms. The most promising disease-modifying strategies on the horizon focus on HTT lowering (Figure), and some examples of these strategies are set to enter clinical trials this year.
One example is the use of zinc finger proteins (ZPFs), which silence transcription of mHTT by selectively binding to the expanded CAG repeat region of the mHTT allele without binding to the wildtype allele. Preclinical testing of this strategy has demonstrated behavioral improvements in an R6/2 mouse model.1
Gene silencing approaches that use small interfering RNA (siRNA) or antisense oligonucleotides (ASOs) to selectively suppress mRNA production also demonstrate significant potential for disease modification. siRNAs and ASOs have both been shown to be safe and effective in HD mouse models, and are now entering human trials. Significant challenges remain for the delivery of these compounds to the human central nervous system (CNS), however, because these compounds cannot cross the blood-brain-barrier. Therefore, vector-assisted, intraparenchymal, intra-cerebro-ventricular, and intrathecal delivery methods are all being explored. Intrathecal delivery appears to be easier and less invasive than other methods. In preclinical testing conducted by Isis Pharmaceuticals, mHtt expression in mouse models was suppressed by up to 52% in the cortex, 64% in the spinal cord, and 20% in the caudate nucleus with an intrathecal ASO called Isis HTT-Rx®. A phase I clinical trial will begin this year to evaluate the compound’s safety in humans.
Alnylam Pharmaceuticals and Medtronic have developed an implantable pump infusion system to deliver ALN-HTT®, an siRNA-based therapeutic, into the putamen. The pump infusion system comprises an experimental catheter and the commercially available Medtronic SynchroMed II® pump. The companies believe that siRNAs will be evenly distributed between the striatum and other regions of the brain.2 This approach was validated in Rhesus monkeys with a continuous infusion of siRNA over 7 days, leading to a 45% reduction of HTT mRNA in the putamen.
Finally, Roche recently described a new delivery approach using a monovalent molecular shuttle they call a “Brain Shuttle” that modifies the binding mode of an antibody to the transferring receptor and increases blood-brain barrier transcytosis.3 Their study demonstrated a 55-fold increase in target engagement using the “Brain Shuttle” to deliver antibodies to beta amyloid in a mouse model of Alzheimer disease. This shuttle system may have the potential to deliver mHTT-silencing compounds in a less invasive manner than those mentioned above.
Several disease-modifying therapies for HD currently in development focus on selectively lowering mHTT in the CNS. As the challenges of CNS delivery and distribution are addressed, the possibility of slowing or reversing the effects of mHTT production may become a reality.
For further reading, please see Dr. Zielonka and colleagues’ “Update on Huntington’s disease: Advances in care and emerging therapeutic options,” published in the March 2015 edition of Parkinsonism and Related Disorders.
1Garriga-Canut M, Agustín-Pavón C, Herrmann F, Sánchez A, et al. Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice. Proc Natl Acad Sci USA. 2012 Nov 6;109(45):E3136-45.
2Zhang Y, Friedlander RM. Using non-coding small RNAs to develop therapies for Huntington’s disease. Gene Ther. 2011 Dec; 18(12):1139-49.
3Niewoehner J, Bohrmann B, Collin L, et al. Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron. 2014 Jan 8; 81(1):49-60.