Gene Therapy for Neurological Disorders: Progress and Challenges

Gene therapy offers a new approach to treating neurological disorders by directly addressing the genetic faults that cause them. While there are still hurdles to overcome, recent advances in delivering genes, editing genes, and targeting specific cells raise the possibility that gene therapy will become a common treatment for neurological diseases.

Challenges of Gene Therapy for the Brain

The blood-brain barrier (BBB) is a major obstacle for gene therapy in the central nervous system (CNS). Traditional methods of delivering genes often struggle to cross the BBB effectively, preventing them from reaching the target neurons. Additionally, ensuring that the delivered genes work for a long time and only affect the intended cells in the complex CNS environment remains a challenge.

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Advancements in Gene Delivery

  • Engineered Adeno-Associated Viral (AAV) Vectors: AAV vectors are a popular choice because they rarely cause immune system reactions and can integrate into the host genome for long-term expression. Recent research has focused on modifying AAV shells to improve BBB penetration and target specific neuronal populations.
  • Non-Viral Delivery Systems: Delivery systems that do not use viruses, such as nanoparticles and those based on polymers, offer an alternative approach with a lower risk of triggering the immune system. However, efficiently and specifically delivering genes to the CNS using these systems is still an active area of research.

Representation of viral and non-viral delivery systems. AAV: adeno-associated virus. NP: nanoparticle. AuNP: gold nanoparticle. CNT: carbon nanotube. MNP: magnetic nanoparticle. MSN: mesoporous silica nanoparticle. QD: quantum dot.

Gene Editing for Neurological Disorders

CRISPR-Cas9 gene editing technology is a powerful tool that can directly correct mutated genes associated with neurological disorders. Studies in animals have shown promise for treating Huntington's disease and Friedreich's ataxia. However, ensuring the safe and efficient delivery of CRISPR systems within the body remains a significant challenge.

CRISPR-Mediated Genome Editing for Neurodegenerative Diseases: Neuroinflammation plays a crucial role in the initiation and progression of various neurodegenerative disorders. Activation of astrocytes and microglia induces the expression of proinflammatory cytokines and chemokines including GMF, IL1-β, IL-6, IL-8, TNF, IL-12, IL-23, IL-33, CXCL10 and CXCL12. Because of neuroinflammation, there is increased phosphorylation of p38MAPK/ERK pathways, which leads to activation, and nuclear translocation of NFκB thereby causing increased oxidative stress, mitochondrial dysfunction and apoptosis (red spheres). These deleterious effects ultimately lead to neurodegenerative disorders and impaired blood brain barrier. The progression of neurodegenerative cascade results in impaired cognitive function and loss of memory. CRISPR/Cas9-mediated genome editing is a powerful tool for inducing gene correction, disease modeling, transcriptional regulation, epigenome engineering, chromatin visualization as well as development of neurotherapeutics. It can be used to increase the levels of anti-inflammatory cytokines (IL-4, IL-6, IL-10, IL-11, IL-13, IL-33, TGFβ, CXCL16) and neurotrophic factors (BDNF, CDNF, GDNF, MANF, NGF, NT3, NT4, NRTN) (blue spheres) which in turn can stimulate the proliferation and expansion of neural stem cells, neurogenesis, gliogenesis, remyelination and neural plasticity thereby ultimately leading to improved cognitive function and memory enhancement

Targeting Gene Therapy

Precisely delivering therapeutic genes to specific neuronal populations is crucial for maximizing effectiveness and minimizing unintended effects. Promising strategies include:

  • Promoter Targeting: Using promoters that are only active in desired cell types ensures that genes are only expressed in target neurons.
  • RNA Interference (RNAi): RNAi technology can silence the expression of disease-causing genes, offering a potential treatment approach for dominant neurological disorders.

Schematic diagram of protein overexpression via AAV in the substantia nigra dopamine neurons. When an AAV carrying protein or RNA is expressed in the brain, particularly in the substantia nigra where dopamine neurons are vulnerable to stress, the consequences of excessive overexpression may result in a number of events detrimental to cell survival. These include the increased formation of stress granules, increased levels of endoplasmic reticulum (ER) stress, activation of the unfolded protein response (UPR), and impairment of the proteasome function and autophagy. This could further result in impairments in vesicle fusion at the synapse and difficulties in the dopamine release and pacemaking functions of the neuron. This would culminate in reduced neuronal activity and may result in the death of the neuron. (BIP: Binding immunoglobulin protein).

Future Directions

Gene therapy for neurological disorders has the potential to revolutionize patient care. Continued progress in vector design, gene editing technologies, and targeted delivery methods is essential to overcome current limitations. Researchers and companies that supply tools for gene therapy research, like Maxanim, are important for developing the technologies needed for these advancements. With ongoing research efforts, gene therapy has the potential to become a reality for a broad range of currently untreatable neurological conditions.


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Gene Therapy for Neurological Disorders: Progress and Challenges
Gen store June 24, 2024
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