What are the current treatments and clinical trials available for Huntington's disease?

Current Treatments and Clinical Trials for Huntington's Disease

There are currently no curative treatments for Huntington's disease (HD), with management focusing primarily on symptom relief through pharmacological and non-pharmacological approaches, while promising gene and cell therapy clinical trials are underway to address the root cause of the disease. 1

Current Pharmacological Treatments

Medications for Chorea

• Tetrabenazine is FDA-approved for treating chorea in HD, with clinical trials showing a statistically significant reduction in Total Chorea Score compared to placebo 2
• Deutetrabenazine (Austedo) and valbenazine (Ingrezza) are also approved for alleviating chorea symptoms in HD patients 1
• When prescribing tetrabenazine, start at 12.5 mg daily and titrate slowly at weekly intervals by 12.5 mg to a maximum of 50 mg/day (or 100 mg/day for extensive metabolizers after CYP2D6 genotyping) 2
• Tetrabenazine carries a boxed warning for depression and suicidality risk, requiring close monitoring, especially in patients with history of depression 2

Medications for Psychiatric Symptoms

• Antipsychotics such as haloperidol, sulpiride, and quetiapine can help manage both chorea and psychiatric symptoms 1, 3
• Antidepressants are recommended for managing depression in HD patients, with amitriptyline and mirtazapine showing some benefit 4
• Risperidone may be helpful for psychosis, while olanzapine, haloperidol, and buspirone can address behavioral symptoms 4

Non-Pharmacological Interventions

• Establish predictable daily routines with consistent timing for meals, activities, and sleep to reduce confusion and anxiety 3
• Create a safe environment by removing hazards and reducing environmental stimuli that may trigger agitation 3
• Use the "three R's" approach (repeat, reassure, and redirect) to manage behavioral disturbances 3
• Break complex tasks into simple steps and provide clear instructions to help patients maintain independence longer 3
• Use visual cues, calendars, and labels to help with orientation 3

Emerging Therapies and Clinical Trials

Antisense Oligonucleotide (ASO) Therapy

• ASO therapy has shown promise in clinical trials by targeting the mutant huntingtin protein (mHTT) at the RNA level 1
• Tominersen (formerly IONIS-HTTRx/RG6042) was the first ASO to enter clinical trials for HD, demonstrating significant reduction of mHTT in cerebrospinal fluid 1
• The phase III GENERATION HD1 trial for Tominersen was halted in 2021 due to unfavorable risk-benefit ratio, though post-hoc analyses suggested potential benefit in younger patients with lower disease burden 1
• Other ASO therapies are in development with improved targeting specificity for mutant HTT while sparing normal HTT 1, 5

Gene Therapy Approaches

• Gene editing techniques aim to correct or delete the mutated HTT gene at the DNA level 1
• RNA interference (RNAi) strategies are being developed to suppress expression of mutant HTT 1, 5
• Small molecule splicing modulators represent another approach to modify HTT expression 1

Cell-Based Therapies

• Cell therapy strategies aim to replace lost neurons or provide trophic support to damaged brain regions 1
• Multifaceted approaches that address various aspects of HD pathology (cell types, epigenetic modifications, genetic factors) are being investigated 1

Common Pitfalls in HD Management

• Overlooking non-pharmacological approaches before initiating medication 3
• Starting medications at too high a dose; the "start low, go slow" principle is essential in HD treatment 3, 2
• Failing to monitor for depression and suicidality, especially when using tetrabenazine 2
• Not considering the potential negative impact of medications on cognition and functional capacity, as seen in tetrabenazine clinical trials 2
• Neglecting personalized management that considers symptom variations, adverse drug reactions, potential complications, and drug interactions 1

Future Directions

• Synergistic treatment strategies that integrate various therapeutic approaches may provide better outcomes 1
• Ongoing innovations in interdisciplinary research are expected to bring significant advancements in HD treatment 1, 5
• The most promising emerging therapies are those aimed at lowering levels of mutant huntingtin protein 5, 6