Illustration credits to Maegha Subramaniam

Gene therapy has rapidly evolved from a theoretical promise to clinical reality, offering new hope for patients with neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s and Motor Neuron disease. These conditions are characterised by progressive neuronal loss, leading to severe cognitive, motor and behavioural impairments. 

Many of these conditions are predominantly sporadic and currently incurable, with treatments focused on symptom control rather than addressing the root cause. Gene therapy has not only the potential to treat conditions with a clear genetic basis, but genetic approaches may be used to provide neuroprotection even in sporadic disease .

How Gene Therapy Works

At its core, gene therapy involves delivering new genetic material into a patient’s cells to modify existing genetic material.  This can replace defective genes, silence harmful genes, or introduce new genes that can produce therapeutic proteins. Delivery is typically achieved using viral vectors, most commonly adeno-associated viruses (AAVs) or lentiviruses, engineered to be both safe and able to infect non-dividing cells such as neurones.  Newer vectors are less immunogenic and can target neurons and glia more precisely.  Non-viral vectors, such as nanoparticles, liposomes, and exosomes also have potential – offering lower immunogenicity, but often reduced efficiency. 

The strategies currently being used for neurodegenerative disorders are summarised below

• Gene replacement: Supplying a functional copy of a defective gene, where there is a clear genetic pre-disposition as in spinal muscular atrophy (SMA),certain inherited forms of ALS (5-10% cases), or Huntington’s disease.

• Gene silencing: Using RNA interference (RNAi) or antisense oligonucleotides (ASOs) to reduce the production of toxic proteins, such as mutant huntingtin in Huntington’s disease.
• Gene editing – Employing CRISPR-Cas9 or similar tools to directly correct harmful mutations in the genome, as used successfully in pre-clinical models of Alzheimer’s, Parkinson’s, (ALS) and Huntington’s. 
• Gene addition: Introducing genes that produce neuroprotective factors and aim to slow neuronal loss, for example in SMA.

Recent Advances and Clinical Trials

In the past decade, several gene therapy approaches have entered clinical trials, with some showing encouraging results:

• Parkinson’s disease: AAV-based delivery of the aromatic L-amino acid decarboxylase (AADC) gene has shown improved motor function in early-phase studies by enhancing dopamine synthesis. 
• Huntington’s disease: AAV-delivered microRNA (AMT-130)  targeting mutant Huntingtin protein in a phase 1/2 trial have shown a 75% reduction in the  mutant protein.  ASO-based therapies, such as those targeting the mutant HTT gene, have successfully reduced mutant protein levels in cerebrospinal fluid, although translating this into clinical benefit remains challenging.
• ALS: Gene-silencing therapies targeting SOD1 mutations have slowed disease progression in some patients, marking a significant milestone for a condition with few effective treatments.
• Alzheimer’s disease: Gene therapy is being investigated to deliver neurotrophic factors or modulate amyloid and tau pathology.  A first-in-human trial of AAV2-BDNF aims to enhance synaptic connectivity in early disease, reflecting an emerging shift toward disease-modifying strategies rather than symptomatic management.

Challenges and Limitations

Despite the promise, several hurdles remain:

1. Delivery barriers: Delivering therapies across the blood-brain barrier (BBB) often requires intrathecal or intracerebral administration, although a number of AAV serotypes (AAV9, AAVrh10 and 8) can cross it effectively.
2. Long-term safety: Concerns remain about immune responses, off-target effects, and the durability of therapeutic benefit.
3. Disease complexity: Many neurodegenerative diseases involve multiple genetic and environmental factors, making single-gene interventions less effective for sporadic cases.
4. Cost and accessibility: Gene therapies are expensive to develop and manufacture, raising questions about equitable access.

The Road Ahead

Looking ahead, combination strategies may prove most effective, pairing gene therapy with small molecules, cell therapy, or immunotherapy. Advances in vector engineering, such as capsids that can cross the BBB more efficiently, and precision gene-editing tools like CRISPR-Cas systems, are expected to expand the range of treatable conditions. Moreover, earlier diagnosis through genetic screening and biomarkers will be crucial, as gene therapy is likely to be most effective before extensive neuronal loss occurs.