**1. Introduction**

Huntington's disease (HD) is genetically inherited in an autosomal dominant fashion. It is a fatal neurodegenerative disease, caused by an abnormal triplet repeat expansion of CAG (cytosine-adenine-guanine) within the huntingtin (*HTT*) gene on chromosome 4p16.3, causing a mutated huntingtin protein (mHTT) [1–5]. HD is predominantly characterized by adult-onset, progressive motor dysfunction, cognitive impairment and psychiatric symptoms (depression, anxiety, obsessive-compulsive disorder, and psychosis). Chorea, incoordination, and rigidity are common motor symptoms due to neurotoxicity of mHTT, leading to brain atrophy of the striatum, thalamus, cerebellum, brain stem and cortex [6–9]. Clinically, HD includes juvenile HD (onset less than 21 years, and marked clinical symptoms), and late-onset HD (after the age of 60 years) [10–12]. Alcohol, drug, and tobacco abuse were associated with earlier onset of HD, and hasten motor onset in women. These abuses have more significant associations in females than in males [13,14]. Children with CAG repeats

≥39, had significantly lower measures of head circumference, weight, and body mass index [15–17]. Disrupted sleep, tics, pain, itching, and psychosis are the common symptoms of juvenile HD [18].

Presently, there is no remedy for HD, and the disease progresses manifests with a presumed continuation of 15–20 years after the appearance of the first symptom [12,19]. The identification of novel biomarkers involves the development of new treatment strategies. The current therapy is palliative and does not change the course of the disease. Tetrabenazine (TBZ; Xenazine™) was approved for the remedy of chorea in HD by the U.S. food and drug administration (FDA). Additionally, the deuterated version of TBZ, deutetrabenazine (AUSTEDO™), has an improved pharmacokinetic profile and was recently approved by the FDA for the treatment of Huntington chorea. In the last review [20], we discussed different promising agents in the treatment of HD, and their phases under clinical trial. Here we describe updates related to these promising agents which will cure HD.

#### **2. Pathogenesis of the HD**

HD is a monogenic disease with prevalence of about 1 in 7,500 individuals in the general population [21,22]. The normal allele has less than 27 CAG repeats and intermediate alleles have 27–35 repeats. CAG repeats of 36–39 will develop HD with less penetrance. Individuals who have 40 or more CAG repeats will develop HD with full penetrance. It is also reported that the higher the CAG expansion, the earlier the onset and the greater the disease severity [12,23]. Kremer et al. reported the largest expansion of 121 trinucleotides [24]. CAG codon encodes glutamine α-amino acid (symbol Gln or Q). Glutamine (C5H10N2O3) is synthesized from glutamate and ammonia by the enzyme glutamine synthetase. It is mainly produced in muscle, the lungs, and the brain and acts as a precursor to the neurotransmitter glutamate [25]. CAG has glutamine amino acids within the *HTT* gene and it is not toxic in itself. However, the polyglutamine expansion involves the formation of aggregate and ultimately becomes toxic. It is the principal factor for the manifestation of HD because aggregates are never a remarkable feature in the brain of normal subjects [26,27]. Aggregate formations are accountable for secondary problems, like inflammatory responses (altered cytokine and nitric oxide level), mitochondrial dysfunction (imbalanced level of free radicals and oxidative stress markers), nuclear cleavage, apoptosis, excitotoxicity, transcriptional altered regulation, and lastly, are responsible for the altered neuropathological feature (cause of cell death/damage) (Figure 1). Approximately 70% of the variation of the disease is due to expanded CAG repeats, while 13% of the variation is due to polymorphisms in the GRIK2 gene [28]. These depict the importance of secondary factors that affect disease onset, its severity, and possible output.

**Figure 1.** Mechanism of Toxicity of Huntingtin (*HTT*) gene. NO (Nitric Oxide), CAG (cytosine-adenine-guanine).

#### **3. Therapeutic Update**

Currently, many drugs are under clinical trial. In the following subsection, we discuss their therapeutic status and their potential role in treatment. These drugs are summarized in Table 1 and Figure 2.

#### *3.1. Drugs against Excitotoxicity*

#### 3.1.1. Riluzole and Memantine Drug

Riluzole is a glutamate inhibitor that reduces abnormal movement in amyotrophic lateral sclerosis (ALS) patients [29,30]. In a double-blinded trial, riluzole did not decrease symptoms of HD, nor was it neuroprotective [31].

Memantine is an antagonist of extrasynaptic N-methyl-D-aspartate (NMDA) receptors and is used for the treatment of moderate-severe dementia in Alzheimer's disease (AD). It diminishes striatal cell death, hinders disease progression and improves cognitive function related to HD [32,33]. The combination of memantine and risperidone prevented the expected progression of motor symptoms, cognitive decline, and psychosis over a 6-month study period [34]. However, memantine dosing may be critical, as rodents on low-dose memantine had decreased pathology, while a high-dose of memantine worsened rodent outcomes and possibly promoted cell death [35–37].

#### 3.1.2. Tetrabenazine (TBZ) and Deutetrabenazine

TBZ inhibits the dopamine pathway by inhibiting vesicular monoamine transporter (VMAT) type 2 and consequently decreases available dopamine in the synapse and its interaction with postsynaptic dopamine receptors [38–40]. Deutetrabenazine contains a deuterium atom and is a novel inhibitor of VMAT2. In indirect treatment comparison studies, deutetrabenazine was found to have a favorable tolerability profile compared to tetrabenazine [41]. In mouse models, TBZ ameliorated chorea and other motor symptoms, and reduced striatal neuronal cell loss [38].

#### *3.2. Targeting Caspase Activities and Huntingtin Proteolysis*
