Huntington’s Disease and C9orf72 ALS: Shared Mechanisms and Therapeutic Hopes

Approximately 70,000 people have been diagnosed with Huntington’s disease (HD) in the U.S. and Europe, with hundreds of thousands more at risk of inheriting the condition. Despite the clear genetic cause of HD, there are currently no approved therapies that delay onset or slow progression.

Both Huntington's disease and C9orf72-linked ALS, while clinically distinct, share a common hallmark: long, abnormal repetitions of DNA bases. The success of antisense oligonucleotides (ASOs) in spinal muscular atrophy (SMA, SMN1 gene) in 2017, followed by gene therapy in 2019, gave researchers confidence to pursue similar strategies in HD and C9orf72 ALS. Progress in treating one of these repeat expansion diseases may provide hope for others.

1. Genetic Basis

1.1 Huntington’s disease (HD)

HD is caused by an expanded CAG trinucleotide repeat in the HTT gene. - Normal alleles: up to approximately 26 repeats - Pathogenic threshold: 36 or more repeats

CAG encodes glutamine, leading to a mutant protein with an expanded polyglutamine (polyQ) tract. This toxic protein disrupts neuronal function and accumulates throughout the body, contributing not only to neurodegeneration but also to systemic issues like muscle atrophy, cardiac problems, impaired glucose tolerance, weight loss, osteoporosis, and testicular atrophy.

1.2 C9orf72 ALS/FTD

C9orf72-related ALS and frontotemporal dementia (FTD) are caused by an expanded GGGGCC (G4C2) hexanucleotide repeat in the C9orf72 gene. - Normal alleles: up to approximately 30 repeats - Pathogenic alleles: hundreds to thousands

The expansion causes disease through several mechanisms: - Reduced C9orf72 protein levels - Formation of toxic RNA foci - Production of abnormal dipeptide repeat proteins via repeat-associated non-ATG (RAN) translation

1.3 Other repeat expansion diseases

• Spinocerebellar ataxias (SCAs) – many caused by CAG expansions
• Fragile X syndrome – CGG expansion in FMR1
• Myotonic dystrophy – CTG expansion in DMPK

2. Therapeutic Approaches: Shared Strategies

2.1 Antisense oligonucleotides (ASOs)

ASOs aim to reduce toxic transcripts. - HD: ASOs targeting HTT mRNA have reached clinical trials (e.g., Roche/Ionis). - C9orf72 ALS: ASOs targeting repeat-containing transcripts are in early-stage trials.

2.2 Gene silencing/editing

The most advanced approach in HD is uniQure’s AMT-130 gene therapy: - Uses an AAV vector to deliver microRNAs designed to silence mutant HTT. - Administered through MRI-guided stereotactic neurosurgery directly into the striatum. - Clinical trials (U.S. and Europe) are ongoing, with promising early results showing up to 75% slowing in disease progression in high-dose patients over 36 months.

These approaches are not yet cures, but they show that disease modification is possible. Advances in vector design (AAVs, lipid nanoparticles) are directly transferable to other repeat expansion disorders.

2.3 Targeting RNA structures

Small molecules that bind abnormal RNA structures (hairpins, G-quadruplexes) are under development for C9orf72 ALS and myotonic dystrophy, with potential extension to CAG-repeat disorders like HD.

2.4 Modulating protein homeostasis

Strategies to boost autophagy, proteasome activity, or molecular chaperones could reduce toxic protein aggregates in both HD and C9orf72 ALS.

3. Translating Progress Across Diseases

Research tools—such as assays for RNA foci, protein aggregation, and repeat instability—are shared across laboratories working on different repeat expansion disorders. Breakthroughs in one disease can therefore be rapidly tested in others.

Delivery challenges are also common: therapies must reach neurons in the brain and spinal cord. Advances in intrathecal ASO delivery or viral vector engineering benefit all disorders in this family.

In summary: Huntington’s disease and C9orf72 ALS/FTD are distinct conditions, but they share a unifying principle: DNA repeat expansions that disrupt RNA and protein homeostasis. Therapeutic strategies—including antisense oligonucleotides, RNA-targeting drugs, and gene-editing technologies—are broadly applicable across these diseases. Progress in one field accelerates progress in others, offering shared hope for patients facing these devastating neurodegenerative disorders.