Clinical Trials researching the treatment of polyglutamine diseases are explored in this section to gain an overall view of the past and current state of clinical development. Around 200 clinical trials have been registered on clinicaltrials.gov over the last 10 years for polyQ diseases, reinforcing not only their low numbers in clinical development but also the rarity of these conditions. Figure shows an oscillating curve equaling seventeen to thirty clinical trials per year for polyQ diseases combined, between the years 2013 to 2023. Huntington's disease dominates in numbers for yearly clinical trials followed by Spinocerebellar ataxia (SCA), Spinal and bulbar muscular atrophy (SBMA), and Dentatorubral-pallidoluysian atrophy (DRPLA). Analysis of PolyQ disease clinical trials reveals that nearly half of all trials for the different indications are not phased (Figure ). The phase that contains the next largest group of trials is Phase II studies for Huntington's disease (HD), Phase III studies for spinocerebellar ataxia (SCA), and both Phase II and Phase III studies for spinal and bulbar muscular atrophy (SBMA). The Dentatorubral-pallidoluysian atrophy (DRPLA) indication contains one clinical trial (NCT05489393) on clinicaltrials.gov which is a global patient registry to establish a database of patient-reported data on individuals affected with DRPLA from around the world. Nearly half of all clinical trials for HD, SCA, and SBMA have been completed (Figure ). The status with the next largest group of trials is the recruiting status with is encouraging as new clinical trials are created and carried out to research the treatment of these rare polyglutamine diseases, offering hope to patients worldwide. Antisense oligonucleotide (ASO) therapeutics in clinical trials for the treatment of HD include tominersen (NCT05686551) and WVE-003 (NCT05032196). After halting a Phase III clinical trial (NCT03761849), post hoc analysis revealed tominersen may benefit young adult patients with lesser disease burden. 241 A new Phase II clinical trial (NCT05686551) was created to research this finding and is currently recruiting participants. Interim results for Phase I/Phase II clinical trial NCT05686551, reveals that a single dose of another ASO, WVE-003 (30 or 60 mg), led to a mean 35% reduction in mHTT in the cerebrospinal fluid compared to a placebo. More upcoming trial findings are expected by June 2024. Another treatment of Huntington's disease is examined with clinical trial NCT05769972. Researchers at Santa Cre Hospital in Spain are recruiting for their study (NCT05769972) to research the use of a computer based cognitive rehabilitation program in patients with HD with expectations that the program will have a greater beneficial effect on the cognitive status of patients compared to control modalities such as music therapy. Sage Therapeutics' and PTC Therapeutics' small molecule drugs PTC518 and SAGE-718 are currently recruiting for their Phase II and Phase II/Phase III clinical trials, respectively. PTC518 modifies RNA splicing, disrupting the production of all HTT protein forms, while SAGE-718 is a NMDA receptor positive allosteric modulator. Clinical trials (NCT05358717, NCT05107128, NCT05358821, and NCT05655520) will research the safety, tolerability, and efficacy of these drugs for the treatment of HD. A previous Phase I clinical trial for PTC518 revealed the drug reduced HTT mRNA in a dose-dependent manner. 244 SAGE-718 has completed initial single and multiple ascending dose clinical studies, where it demonstrated efficacy in disease-relevant populations. In addition, SAGE-718 was granted both FDA Fast track designation 246 in 2022 and FDA Orphan Drug Designation in 2023. Phase I and Phase II/Phase III clinical trials (NCT02728115 and NCT04219241) assessing the safety and efficacy of Cellavita's NestaCell, a stem cell therapy derived from immature human dental pulp, are currently active for the treatment of Huntington's disease. Another Phase III clinical trial (NCT06097780) researching NestaCell is not yet recruiting but has an estimated start date of June 2024. A previous Phase I clinical trial revealed no serious adverse events and improved HD motor manifestations for the treatment of HD with NestaCell.