BackgroundAutonomic dysfunction has been reported in Huntington's disease (HD), but its extent and mechanisms remain unclear. This study aimed to evaluate autonomic function using standardized cardiovascular autonomic reflex tests (CRTs) in a cohort of genetically confirmed HD patients.MethodsIn this single-center, cross-sectional study, we assessed 16 patients with manifest HD using head-up tilt test (HUTT), Valsalva maneuver (VM), deep breathing test, cold face test, and handgrip test, all performed under continuous blood pressure (BP) and heart rate (HR) monitoring. Age- and sex-matched healthy controls (HC) were included for comparison.ResultsBased on medical history, 56% of HD patients reported symptoms of orthostatic intolerance while standing. During HUTT, they showed a significant reduction in ΔBP. BP overshoot during VM was also significantly reduced. HR responses and BP changes did not differ significantly between groups across all other maneuvers. When stratified by disease stage, parasympathetic indices were lower in later-stage patients.ConclusionsHD patients exhibited subclinical adrenergic abnormalities on CRTs, with initially preserved cardiovagal control, a pattern compatible with central autonomic involvement and possible progressive impairment of both sympathetic and parasympathetic systems over time.
In this edition, we highlight several important developments across the Huntington's disease therapeutic pipeline. We discuss the launch and subsequent discontinuation of POINT-HD, the first-in-human phase I study of RG6496 (Hoffmann-La Roche), an allele-selective antisense oligonucleotide designed to selectively lower mutant huntingtin while largely preserving wild-type huntingtin expression. We also discuss the launch of two phase III efficacy trials: INVEST-HD, evaluating votoplam (Novartis Pharmaceuticals), and PRECISE-HD, evaluating pridopidine (Prilenia). In addition, we summarise recent advances across the field, including preclinical updates for LQT-23 (LoQus23), SRP-1005 (Sarepta Therapeutics) and HRN001 (Harness Therapeutics); interim 12-month clinical results from SKY-0515 (Skyhawk Therapeutics); the announcement by uniQure that 3-year data from the phase I/II AMT-130 study may support a Biologics License Application seeking accelerated approval and Roche's discontinuation of the phase II GENERATION HD2 study of tominersen. Finally, we provide an updated listing of registered and ongoing clinical trials in Huntington's disease.
Huntington's Disease (HD) is a progressive neurodegenerative disease that is caused by a CAG-repeat expansion in the exon 1 of the huntingtin ( HTT ) gene, which results in the formation of toxic mutant HTT (mHTT) exon 1 fragments with expanded polyglutamine (polyQ) stretch. These mHTT fragments are prone to misfolding and aggregation, causing cytotoxicity, particularly in the striatal neurons. The lack of disease-modifying treatments for HD emphasizes the need to develop new therapeutic strategies to prevent or reverse HD pathology. The reduction of the mHTT exon 1 fragment by facilitating its selective degradation may be a promising approach to prevent aggregation, thereby delaying or preventing the onset of HD. Since the ubiquitin-proteasome system (UPS) is not impaired in HD, enabling strategies to selectively target mHTT towards the UPS or autophagy would improve mHTT clearance. In this review, we describe three main strategies to modulate mHTT levels. First, we discuss different ubiquitin-modifying enzymes that have been associated with HTT and may act as possible therapeutic targets. Next, we focus on more targeted approaches for the selective degradation of mHTT with engineered small molecule compounds such as PROTACs and AUTOTACs. Finally, we summarize the current knowledge of HTT-specific intracellular antibodies (intrabodies) as potential candidates for gene therapy. Together, this review aims to assess different possible avenues for the treatment of HD.
Chaperone-assisted selective autophagy (CASA) is a crucial process aimed at maintaining proteostasis in several neurodegenerative diseases associated with protein misfolding, including polyglutamine (polyQ) diseases. Autophagy is a critical lysosome-mediated degradation pathway, particularly essential in neurons, which are highly susceptible to proteotoxic stress due to their post-mitotic nature. Selective autophagy pathways, including CASA, ensure the targeted removal of misfolded proteins and damaged organelles, thereby preserving cellular homeostasis. CASA is based on the intersection of chaperones and autophagy, where HSPB8 and BAG3 interact with HSPA and STUB1 forming a complex that identifies, ubiquitinates, and directs aberrant proteins toward autophagosomes for subsequent lysosomal degradation. In polyQ diseases, such as spinal and bul muscular atrophy (SBMA) and Huntington's disease (HD), mutant proteins accumulate, overwhelming the protein quality control systems. The CASA components are upregulated as a compensatory response, promoting toxic aggregates clearance and cellular damage mitigation. However, chronic proteotoxic stress and progressive impairment of autophagic and lysosomal pathways eventually limit CASA efficiency, contributing to disease progression. The review highlights how CASA exerts its protective activities in polyQ diseases and reports therapeutic strategies aimed at enhancing CASA activity, including pharmacological inducers and combinatorial approaches targeting autophagy and the ubiquitin-proteasome system. Overall, CASA emerges as a crucial adaptive mechanism and a promising therapeutic target in polyQ-related neurodegeneration.
Emerging evidence suggests a central and early role of mitochondrial dysfunction, including altered mitochondrial dynamics, in Huntington's disease (HD) pathogenesis. Processes such as mitochondrial fission, fusion, transport and mitophagy are vital for proper mitochondrial function and seem to be key mediators of neuronal vulnerability in HD. In this review, we summarize mechanistic insights into mitochondrial dynamics in HD, highlighting how mutant huntingtin (mHTT) impairs mitochondrial biogenesis and morphology, disrupts Drp1-dependent fission, compromises fusion, transport and organelle crosstalk with the endoplasmic reticulum, and disrupts mitochondrial quality control, ultimately leading to neuronal degeneration. Since these alterations correlate with bioenergetic deficits, calcium dysregulation and oxidative stress, we highlight how altered mitochondrial dynamics contribute to and possibly drive HD pathogenesis. Furthermore, we discuss how mitochondrial dynamics in HD can be altered based on cell type specificity, experimental model and disease stage.
