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Review
. 2019 Mar 8:9:3-17.
doi: 10.2147/DNND.S163808. eCollection 2019.

The effects of huntingtin-lowering: what do we know so far?

William F Kaemmerer  1 , Richard C Grondin  2
Affiliations
Review

The effects of huntingtin-lowering: what do we know so far?

William F Kaemmerer et al. Degener Neurol Neuromuscul Dis. .

Abstract

Therapies targeting mutant huntingtin DNA, mRNA, and protein have a chance at becoming the first disease-modifying treatments for Huntington's disease, a fatal inherited neurodegenerative disorder for which only symptom management treatments are available today. This review focuses on evidence addressing several key questions pertinent to huntingtin-lowering, ranging from the functions of wild-type huntingtin (wtHTT) that may be disrupted by huntingtin-lowering treatments through the various ways huntingtin can be lowered, the tolerability of wtHTT-lowering in mice and primates, what has been found in the Ionis Pharmaceutical safety trial of a huntingtin-lowering therapy, and to the question of how much mutant huntingtin may need to be lowered for a therapy to be clinically effective. We conclude that adverse consequences of lowering wtHTT in animals appear to be brain region-specific, and/or dependent upon the animal's stage of development and the amount by which huntingtin is lowered. Therefore, safe approaches to huntingtin-lowering in patients may be to lower huntingtin only moderately, or lower huntingtin only in the most affected brain regions, or lower huntingtin allele-selectively, or all of the above. Many additional questions about huntingtin-lowering remain open, and will only be answered by upcoming clinical trials, such as whether the delivery approaches currently planned will be adequate to get the treatment to the necessary brain regions, and whether non-allele-selective huntingtin-lowering will be safe in the long run. Meantime, there is a role for preclinical research to address key knowledge gaps, including the effects of non-allele-selective huntingtin-lowering on protein trafficking and viability at the cellular level, the tolerability of wtHTT-lowering in the corticostriatal connections of the primate brain, and the effects of this lowering on the functioning of neurotransmitter systems and the transport of neurotrophic factors to the striatum.

Keywords: CAG repeat disorder; Huntington’s disease; cortex; gene therapy; huntingtin-lowering; striatum.

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Conflict of interest statement

Disclosure Neither author has any financial, advisory, investment or other relationship with any of the companies mentioned in this article, nor with any other company developing a therapy for HD. WFK is a member of the Scientific Advisory Board of Alcyone Lifesciences, Inc., which makes catheters for the delivery of therapies to the brain via neurosurgery and to the CSF via lumbar puncture, and a co-founder of the CGTA Research Group. The latter organization is a 501(c)3 not-for-profit public foundation dedicated to facilitating the development of treatments for rare diseases affecting the CNS. The authors report no other conflicts of interest in this work.

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