Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease that affects motor neurons or nerve cells that control muscle movement. There is currently no cure for ALS but there are experimental treatments, including gene therapy.

ALS and genetics

In ALS, some genes are known to be modified or mutated, which can harm nerve cells in different ways.

A mutated gene can cause damage by producing toxic accumulation of the gene’s protein product. For example, a modified protein is sometimes not able to fold correctly and tends to form aggregates that are harmful to cells. In this case, one mutated gene copy from a parent can cause considerable damage, even if the second copy from the other parent is still normal.

Therefore, ALS is often inherited in an autosomal dominant manner, and may develop if a child receives one mutated copy from a parent. This situation is more common in familial ALS (FALS).

FALS is less commonly inherited in an autosomal recessive manner, which means that a child would develop the condition if he or she inherited two faulty copies of the gene, one from each parent. Because cells have two copies of each gene, one functional copy is usually sufficient for the child not to inherit FALS.

A mutated gene can encode a protein that’s dysfunctional, thereby causing damage. If the protein is vital for the survival of the cell, a lack of function can have dramatic consequences.

Even though genetics seems to play a role in the development of ALS, disease-causing mutations cannot be identified in most cases.

How gene therapy works

Gene therapy modifies specific genes within a cell through different approaches. If a genetic mutation causes the accumulation of misfolded protein aggregates, a downregulation, or silencing, of the gene may be beneficial. If a genetic mutation results in a loss of function of the protein, delivery of a healthy copy of the gene may reverse the damage.

Gene silencing

The most common genes that are mutated in ALS — C9orf72, SOD1, TARDBP, and FUS — are known to cause damage by resulting in protein aggregates, or clumps. Silencing of the mutated copies of these genes is the subject of current research.

The company UniQure developed miQURE to silence the mutated C9orf72 gene. miQURE is currently being investigated in preclinical studies.

Ionis Pharmaceuticals and Biogen developed IONIS-SOD1Rx (BIIB067), which is designed to silence the mutated version of the SOD1 gene. The therapy is currently in clinical trials.

Delivery of nerve-supporting genes

Because loss of function is rare in FALS, gene therapy to replace an nonfunctional gene copy is not being widely investigated. Instead, the delivery of other genes that can preserve nerve cell function, irrespective of mutations, is being explored. This therapeutic approach may benefit patients in whom disease-causing mutations cannot be identified.

VM BioPharma developed VM202, which is designed to deliver a plasmid that encodes for a protein called HGF. The protein triggers blood vessel formation and nerve growth. VM202 is currently being investigated in clinical trials.

CavoGene LifeSciences is developing SynCav1, currently in preclinical trials, to promote the delivery of a gene that encodes for the caveolin-1 protein, which plays a vital role in neuronal communication.

How genes are delivered to the body

One way to deliver genes to body cells is to use genetically modified stem cells, an advancement of stem cell therapy. Stem cells have the capability to develop into any kind of cells, including motor neurons or glial cells (cells that surround and support neurons).

Another way to deliver genes is with the help of viral vectors that are directly injected into the body. Gene therapy makes use of the ability of viruses to insert their genes into a cell. Harmful genes in viruses are replaced with a gene that has a therapeutic benefit. Then these viral vectors can be injected into different parts of the body, specifically into the spinal cord or muscles in ALS, where they help regenerate muscles and damaged motor neurons.


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