Can Gene Therapy Help Treat Brain Diseases?

Post by D. Chloe Chung

What is gene therapy?

The goal of gene therapy is to alleviate disease symptoms and ultimately cure diseases by correcting abnormal gene expression. This can be done by introducing genetic materials that express exogenous genes or suppress the expression level of endogenous genes in an effort to modify gene expression levels. Gene therapy can be also designed to directly edit gene mutations present in patients. Over the past years, development of novel gene-editing tools has resulted in improved efficacy of gene delivery to the brain. With this exciting technical advancement, gene therapies have recently gained more attention as a potential therapeutic strategy for neurodevelopmental and neurodegenerative diseases, especially for those caused by genetic mutations that disrupt the body’s usual patterns of gene expression.

Different strategies behind gene therapy

There are several ways to design gene therapy to correct aberrant gene expression in neurological diseases. One of them is to express exogenous proteins that can restore the function of faulty endogenous proteins. For this purpose, the adeno-associated virus (AAV) is a preferred viral vector because of its relative safety as well as its long-term gene expression which reduces the need for repeated administration. After being introduced into cells, AAVs can express genes that they carry by using the transcriptional and translational machinery in the host cells. In this way, AAVs produce proteins that can make up for the loss of gene function. The virus engineering field continues to refine structures of AAVs to increase their safety as well as effectiveness in delivery to the central nervous system.

DNA-editing is also an appealing approach for gene therapy as it can directly fix disease-causing mutations and modify gene expression level. The newest advancement in DNA-editing tools involves the synthetic CRISPR system (an abbreviation for ‘clustered regularly interspaced short palindromic repeats’) in which a customized guide RNA can bring a DNA-cutting enzyme (e.g., Cas9) to the specific site within the gene of interest. Once the enzyme cuts out a few base pairs from the gene, the gene sequence will eventually shift and create a premature stop codon). The cellular mechanism takes this stop codon as a sign to degrade messenger RNAs transcribed by this gene, ultimately silencing the expression of the target gene. This genetic tool has great potential to treat neurological diseases as it can be used to inactivate or activate genes of interest, or to edit precise bases within the gene and correct pathogenic gene mutations.

In addition to DNA-editing tools, the RNA-based therapy utilizing antisense oligonucleotides (ASOs) has gained much attention for its potential efficacy. ASOs are short DNA or RNA fragments that can bind to messenger RNAs based on the complementary sequence, subsequently changing the RNA expression level. As such, ASOs can be synthesized to target messenger RNAs transcribed from the disease gene of interest in hopes to regulate the protein level that could play crucial roles in neurological diseases.

How is gene therapy treatment for neurological diseases going?

In 2017, a groundbreaking study published in The New England Journal of Medicine reported the successful usage of gene therapy in young children with spinal muscular atrophy (SMA) type 1, a devastating neuromuscular disease characterized by motor neuron degeneration and progressive muscle loss. In SMA, a defective gene SMN1 reduces the amount of functional SMN1 protein, so researchers treated SMA patients with a one-time blood infusion of AAV that can express the SMN1 gene and restore protein expression level. Excitingly, most of the patients who received this gene therapy showed drastic improvement in their survival and motor functions that lasted through the 2-year follow-up assessment. Some of the patients were even able to walk with no assistance, which is a striking development considering that many SMA patients need wheelchair assistance and die at a very young age.

As of August 2021, a medication designed to increase the level of SMN protein is the only disease-modifying gene therapy approved by the US Food and Drug Administration (FDA) to treat neurological symptoms. Yet, in addition to this medication, numerous preclinical and clinical studies are actively investigating the safety and efficacy of gene therapy for a wider range of neurological diseases. For example, ASOs targeting the gene that makes tau, a protein that becomes abnormally aggregated in Alzheimer’s disease, have been tested in mouse models. After demonstrating their ability to reduce tau pathology and subsequently rescue behavioral deficits in a mouse model, the ASO-mediated tau-targeting gene therapy is being tested in a clinical trial for Alzheimer’s disease patients.

Similarly, ASO-based gene therapy has been investigated for its potential benefits in patients of Huntington’s disease, which is caused by an abnormal trinucleotide expansion in the huntingtin gene. The idea behind this therapy is to use ASOs either to globally target the total huntingtin gene level or to specifically reduce the function of the mutant allele. Based on promising results from preclinical studies, several ASOs entered clinical trials to evaluate their safety and efficacy for Huntington’s disease patients. Unfortunately, however, a couple of these clinical trials have been recently discontinued due to lack of evidence of anticipated benefits for patients.

What are the challenges and what is the hope for the future?

Perhaps the biggest challenge in utilizing gene therapy to treat neurological diseases is safety. For example, when genetic materials are being delivered at a high dosage, they can cause toxicity in patients. Also, undesirable immune responses can occur upon introduction of genetic materials. As these scenarios can lead to fatal consequences, safety is always the first aspect to consider and monitor when designing gene therapy and testing it in clinical trials. Moreover, off-target effects – unwanted changes in genes that were not the target of gene therapy – are also a potential concern. This can happen when ASOs or gene-editing tools target alternative genes based on partially complementary sequences. How to avoid off-target effects can be a major challenge when designing the reagents.

Despite these many challenges, biomedical techniques that improve our ability to utilize gene therapy to effectively treat neurological diseases continue to advance. For instance, delivery of AAVs into the central nervous system used to be highly challenging in the past, since it is not feasible to directly inject AAVs into the brain. At the same time, the blood-brain barrier firmly isolates the brain from the periphery, making it difficult for locally delivered reagents (e.g., injection into blood vessels) to bypass this physical barrier and reach the brain. Yet, characterization of various AAVs and persistent efforts in virus engineering allowed for development of a specific AAV that can be successfully and non-invasively (e.g., without surgeries) delivered to the central nervous system. This type of AAV was also used in designing the effective gene therapy for SMA patients as described above, demonstrating that technological advancement can lead to breakthrough therapeutic strategies. With rapidly evolving gene-editing tools, it's an exciting time for the development of gene therapy for neurological diseases.

References

Sun & Roy. Gene-based therapies for neurodegenerative diseases. Nature Neuroscience (2020). Access the original scientific publication here.

Martier & Konstantinova. Gene therapy for neurodegenerative diseases: slowing down the ticking clock. Frontiers in Neuroscience (2020). Access the original scientific publication here.

Bennett et al. Antisense oligonucleotide therapies for neurodegenerative diseases. Annual Review of Neuroscience (2020). Access the original scientific publication here.

Mendell et al. Single-dose gene-replacement therapy for spinal muscular atrophy. The New England Journal of Medicine (2017). Access the original scientific publication here.

DeVos et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Science Translational Medicine (2017). Access the original scientific publication here.

Kordasiewicz et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron (2013). Access the original scientific publication here.

Southwell et al. In vivo evaluation of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotides. Molecular Therapy (2014). Access the original scientific publication here.

Kwon. Failure of genetic therapies for Huntington’s devastates community. Nature News (2021). Access the news article here.

Hudry & Vandenberghe. Therapeutic AAV Gene Transfer to the Nervous System: A Clinical Reality. Neuron (2019). Access the news article here.

Doudna. The promise and challenge of therapeutic genome editing. Nature (2020).Access the news article here.