3.9.9. Laquinimod

Laquinimod reduces the expression of Bax, responsible for the release of cytochrome C from mitochondria and activation of caspases, causing apoptosis and production of toxic mHTT fragments. This drug improves motor function and reduces depressive behaviors in mice. It is recently undergoing a phase II clinical trial in human HD patients [149]. Laquinimod ameliorates myelination deficiency and behavioral deficits in the YAC128 mouse model of HD [150,151].

#### 3.9.10. Kynurenine Inhibitors

The enzyme indoleamine 2,3 dioxygenase (IDO1) catalyzes the conversion of tryptophan into kynurenine. Kynurenine is then metabolized into 3-hydroxykynurenine (3-HK) and quinolinic acid, both of which are neurotoxic and are increased in HD. In contrast, kynurenine is also metabolized into kynurenic acid, which is neuroprotective. In HD, an imbalance exists between the neurotoxic products and neuroprotective products and targeting the rate-limiting step of IDO1 could effectively shift the balance toward neuroprotective [152]. Kynurenine 3-monooxygenase is the enzyme that catalyzes the conversion of kynurenine into 3-HK. Treating microglial cells from R6/2 mice with a kynurenine 3-monooxygenase inhibitor (Ro 61–8048) showed dramatically reduced 3-HK levels compared to the vector containing cells [153].

#### **4. Conclusions and Future perspectives**

The current therapeutic investigations of HD mainly focus on excitotoxicity, dopamine pathway, caspase inhibitors, mHTT aggregation, mitochondrial dysfunction, transcriptional dysregulation, and diet. The application of robust molecular imaging and digital biomarkers may provide a valuable therapeutic boost to the design of clinical trials. Additionally, the increased openness of regulatory agencies for e ffectiveness will also promote the development of clinical trials. The advancement of modern technologies, and the availability of various promising agents/molecules enable the development of therapies which will further improve the quality of research and outcomes in HD patients. The most promising drugs are those that target the production of mHTT protein and block its actions.

**Author Contributions:** Conceptualization, A.K., V.K. J.-J.K.; methodology, A.K., V.K.; writing—original draft preparation, A.K., V.K.; writing—review and editing J.-J.K., S.K., V.K., Y.-M.L., Y.-S.K., A.K., K.S. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflicts of interest.
