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Gene Therapy As The Possible Key To A Cure For Motor Neuron Diseases

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Motor neuron diseases (MNDs) are a group of neurodegenerative diseases with progressive degeneration of motor neurons (MNs) that lead to muscle weaknesses, loss of ambulation, and chronic disability, ultimately causing premature death in patients (Cappella et al., 2019). Two representative examples are spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), both severe MNDs that share pathological, cellular, and genetic similarities (Tosolini & Sleigh, 2017). They are currently treated with gastrostomy tube placement and non-invasive positive pressure ventilation, which improve symptoms and patients’ lifespan, but do not have a complete cure. Gene therapy became a promising option when the causative gene linked to ALS was discovered, the challenge being determining the therapeutic target and the method of application. The ultimate goal for any type of gene therapy is stopping the selective death of MNs. This essay aims to outline the different types of gene therapy currently under development for SMA and ALS, as well as the potential gene therapy has for providing a substantial cure for diagnosed patients.


SMA is an autosomal recessive disease characterized by limb weakness and respiratory muscle atrophy (Chiriboga et al., 2016). It is caused by reduced levels of survival motor neuron (SMN1) proteins found in almost all cells, leading to degeneration of lower motor neurons in the spinal cord ventral horn. In more severe manifestations, pathology in additional cells and tissue can also be observed (Tosolini & Sleigh, 2017). SMA patients display defined deletion mutations in SMN1, which make it the desirable target of gene therapy. The main approach is to achieve neuroprotection, and testing animal models with viral-vector mediated SMN1 gene replacement showed varying efficacy depending on the time of intervention and the biodistribution of the transgene (Federici & Boulis, 2012).

In 2016, the use of a splice-switching antisense oligonucleotide – nusinersen – was approved by the FDA for use in the USA (Tosolini & Sleigh, 2017). Nusinersen promotes inclusion of exon 7 in SMN1 gene by binding to its pre-mRNA and increases SMN levels. Nusinersen was delivered via intrathecal injection directly into the cerebrospinal fluid (CSF) to overcome the blood-brain barrier. Testing in mice subjects proved that it increased the production and function of SMN protein, and the first human trial involving patients aged 2-14 years with childhood SMA did not result in any serious adverse events, 89% of the participants reporting only a mild headache. No immunogenic responses were found in patients at 9-14 months after a single dose (Chiriboga et al., 2016). The results suggest that nusinersen as a clinical treatment for SMA seems positive in a risk-benefit analysis, and further studies could be carried out to determine the optimal dosage and delivery method.


ALS, also known as Lou Gehrig’s disease, is a fatal, progressive MND characterized by MN degeneration in the motor cortex, brainstem, and spinal cord accompanied by neuroinflammation (Federici & Boulis, 2012; Tosolini & Sleigh, 2017). While 90% of ALS patients are afflicted with the sporadic form (sALS), only 10% are afflicted with the familial form (fALS) linked to a specific gene mutation, the two most prevalent mutations occurring in SOD1 and C9orf72 genes. The SOD1 gene protects cells from reactive oxygen species, and the neurotoxic gain-of-function triggered by mutant genes (i.e., mitochondrial damage) is translated to the phenotype of patients. The C9orf72 gene in ALS patients is characterized by a longer GGGGCC hexanucleotide repeat expansion (HRE) in the first intron than healthy subjects, which causes the downregulation of gene expression and loss of function. The aggregation of HREs in the cell sequester RNA-binding proteins (RBPs) into intra-nuclear RNA foci and disrupt neuronal integrity preservation (Nussbacher et al., 2019). Lastly, the repeat-containing RNAs move to the cytoplasm and are translated into dipeptide repeat proteins which are also aggregation-prone. Since it is unclear which is the main cause of C9orf72 toxicity, studies on gene therapy would have to approach all three possibilities (Cappella et al., 2019).

Another possible therapeutic target are astrocytes, which play a role in ALS by triggering apoptotic and inflammatory reactions in motor neuron cells. Impaired astrocytes lead to excitotoxicity, where motor neurons are adversely affected by reduced levels of glutamate uptake. Thus, enriching normal astrocytes in ALS patients could be a clinical strategy (Federici & Boulis, 2012).

Non-Vector-Based Gene Therapy

Non-invasive approaches include peripheral intramuscular or intraneural administration, which have proven to be inefficient in large animal species due to miniscule gene expression. While this method has shown promising results in mice, it is yet to be validated as a clinical treatment for humans (Federici & Boulis, 2012).

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Viral Vector-Based Gene Therapy

After testing for various virus-mediated gene transfers that can overcome the blood-brain barrier, vectors derived from lentivirus (LV) and adeno-associated virus (AAV) proved to be the most efficient in neuron transduction. LV testing in ALS mice models have been successful – for example, the transfer vascular endothelial growth factor (VEGF) to motor neurons via LV prolonged the survival of subject mice and prevented cell death. Furthermore, treatment using LV successfully restored human SMN protein levels in SMA fibroblasts (Azzouz, 2006). However, while LV has advantages such as its large cloning capacity, difficulties such as unselective tropism and low viral titre limit its use is gene therapy (Cappella et al., 2019). AAV is a non-enveloped, single-stranded, DNA-containing virus that can mediate long-lasting gene transduction of both dividing and non-dividing cells. Research found that the vector is highly translationable in the CNS and the spinal MNs (Federici & Boulis, 2012). Importantly, AAV also displays several crucial advantages: higher safety profile, larger vector spread, and higher transgene levels. These benefits reduce the possibility of clinical viral insertion leading to mutagenesis (Cappella et al., 2019).

For SOD1 fALS, RNA interference has been proposed as a method to nullify the toxic gain-of-function by selectively silencing the mutant SOD1 allele and inhibiting gene translation. Knocking down different cell types allowed for the distinction of their roles in ALS pathogenesis, but while SOD1 silencing significantly increased the lifespan of mice subjects, this has not been proven to be enough to prevent disease progression entirely. A study to assess the safety of an antisense oligonucleotide-based drug is currently underway by ISIS Pharmaceuticals Inc. which will aim to inhibit SOD1 production (Federici & Boulis, 2012).

Genome Editing

The possibility of genome editing has also been suggested. Researchers are evaluating the use of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system to precisely edit the defective parts of the genome by altering, removing, or adding sections of DNA. It is currently the most precise and simplest way of genomic manipulation, but its effects on aspects such as target specificity and immunogenicity need to be ensured before conducting any trial tests on patients (Cappella et al., 2019).


As seen above, varying approaches of gene therapy attempt to address the problems that arise in administration – i.e., determining the timing of therapeutic intervention, delivery method, therapeutic target, consideration of adverse side effects, etc. Research on human subjects have been extremely limited, and while mice provide the conditions for proof-of-principle studies, they do not present a perfect replica of realistic human symptoms (Federici & Boulis, 2012). While gene therapy is the most promising treatment for fALS and SMA, most cases of ALS are sporadic and do not have defined gene abnormalities that can be corrected. The key to treating sALS lies in regulating neurotrophic factors that play important roles in neurogenesis, neuroplasticity, injury of the nervous system, etc. Studies demonstrated that insulin-like growth factor 1 (IGF-1) reduced the pathological activity of non-neuronal pathological cells in SOD1 mice (Cappella et al., 2019).

However, the distinction between sALS and fALS is not clearly delineated as large-scale genetic screening is not yet prevalent and accessible in everyday clinical practice, which would enable precise determination of abnormal genes out of the diverse mutations of ALS. Distinguishing disease-causative genes and genes simply associated with ALS is also a difficulty as many cases result from more than one risk variant. Some sALS cases have oligogenic and polygenic inheritance, causing some isolated cases of fALS to falsely appear as sALS (Mathis et al., 2019).


Despite the many challenges and difficulties that gene therapy is facing, the development and breakthroughs in the past decade seem to increase validation of gene therapy as the road to a potential cure for motor neuron diseases. Currently gene therapy is limited to experimental treatments instead of providing a cure, but once research leads to the discovery of more efficient vectors and the analysis of where, what, and when the therapy should be administered is carried out, it seems highly likely that the benefits of gene therapy would only increase (Tosolini & Sleigh, 2017). The next step in advancement towards a cure is testing the various possible solutions to current problems, which will require the development of appropriate technology to make it feasible – and accessible – for patients.

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Gene Therapy As The Possible Key To A Cure For Motor Neuron Diseases. (2022, February 17). Edubirdie. Retrieved February 5, 2023, from
“Gene Therapy As The Possible Key To A Cure For Motor Neuron Diseases.” Edubirdie, 17 Feb. 2022,
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