3.5.2. HDACi4b

HDACi4b (a pimelic diphenylamide HDAC inhibitor) improves motor impairment as well as decreases neurodegeneration in mouse models of HD. Oral administration of HDACi4b to mice showed improvement in these motor deficits. These mice also showed less striatal atrophy and brain-size reduction. HDACi4b reversed hypoacetylation of the H3 histone subunit that occurs in the presence of mHTT, and mRNA expression was returned to normal levels [63].

#### 3.5.3. Suberoylanilide Hydroxamic Acid (SAHA)

Histone acetylation in the brain is increased by SAHA (by inhibiting HDAC) which improves motor impairments in transgenic R6/2 mice. SAHA can be taken orally because it crosses the BBB, however, this has not been tested in humans [64].

#### 3.5.4. Mithramycin and Chromomycin

Treatments with mithramycin and chromomycin (anthracyclin derivatives) promote epigenetic histone modifications in cultured R6/2 and N171-82Q transgenic cell lines, providing a basis for clinical trials for HD [65,98,99].

#### *3.6. Agents Targeting Mutant Huntingtin*

3.6.1. RNA Interference (RNAi) and Antisense Oligonucleotide (ASO)

ASO and RNAi execute their knockdown function by allele and nonallele-selective manners [100–102]. As an example, modified ASO (peptide nucleic acid i.e., PNA) enables the selective recognition of the mutant allele and selective inhibition of mHTT expression in human fibroblasts [103]. RNAi reduced neuropathology, improved motor behavior and extended viability in HD [102,104,105].

#### 3.6.2. Intrabodies and Artificial Peptides

In transgenic mouse models of HD like R6/2, N171-82Q, YAC128, and BACHD, treatment with intrabody gene therapy improved body weight, motor function, cognitive, and neuropathological manifestation [66,106].

#### *3.7. Nucleic Acid-Targeting Therapies*

#### 3.7.1. Therapies Targeting DNA

Currently, zinc finger proteins (ZFPs) and CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR-associated system) are under investigation.
