25 March 2021

Biotech company PepGen presented the latest data from their research into a new exon skipping treatment for Duchenne muscular dystrophy (DMD) and Myotonic dystrophy type 1 (DM1) at the 2021 Muscular Dystrophy Association Clinical and Scientific Conference last week. 

Their approach, called Enhanced Delivery Oligonucleotide (EDO), has shown positive results in pre-clinical studies. When tested in animal models of DMD, it proved to be safe and led to increased levels of dystrophin. It has also seen positive results in non-human primate studies. PepGen therefore expect to be able to trial EDO in humans by early 2022. Duchenne UK was an early investor in this technology and welcomes this early promising data.

Exon skipping is a treatment approach which aims to correct genetic mutations which can cause DMD, allowing cells to produce functional dystrophin. The dystrophin gene is made up of 79 pieces called exons that link together to form a code. If there is a mutation or fault in one or more exons, they may no longer fit together and the cell machinery cannot ‘read’ their genetic code. The result is that the body produces little or no dystrophin. Exon skipping drugs hide or ‘patch’ the missing pieces of genetic code so that the exons fit together and can be read. Learn more about exon skipping here.

To date, exon skipping has been moderately successful. However, efficacy is low and there are still areas of the body where the treatment is unable to reach and restore function, such as the heart and brain. Exon skipping is also mutation-specific, meaning a new therapy needs to be developed for each mutation. PepGen’s research is looking at Exon 51, but there are other exon skips in development.

PepGen’s exon skipping construct has so far shown that there is strong delivery to all muscle cells – including skeletal, heart muscles and the central nervous system. After a single dose in mice who have a form of DMD (called mdx mice), the drug led to a 54% increase in dystrophin in the leg muscle and a 12% increase in the heart muscle.

As funders of PepGen’s EDO research in 2016 and 2018, Duchenne UK is very pleased to see these positive initial results. By demonstrating strong results in animal models, EDO will be able to begin clinical trials in humans, potentially leading to a safer and more effective exon skipping treatment.

For more information, read PepGen’s press release here.

 

Q & A

What is an Enhanced Delivery Oligonucleotide?

PepGen’s exon skipping construct is made from an enhanced delivery peptide and a therapeutic oligonucleotide:

  • A peptide is made of amino acids, which are the building blocks of proteins. Among other things, they are used to build strength and muscle mass. Previously these haven’t been used as there were unacceptable side effects compared to the benefits of treatment.
  • The oligonucleotide is a short DNA or RNA strand which can be manufactured. This helps to make sure that the peptide is able to target specific cells, such as muscle cells.

Will exon skipping treatments work for everyone with DMD?

Not all DMD patients will be able to benefit from exon skipping treatments. However, data suggests that over 80% of DMD patients have genetic material that is responsive to exon skipping.

However, one of the challenges of exon skipping is that it is not a ‘one size fits all’ solution, as different people will require a different exon to be skipped. Current research suggests that 14% of DMD patients require exon 51 to be skipped, 10% require exon 53, and 9% require exon 45.

What exon skipping treatments are currently available?

A treatment called Etiplersen (under the brand name EXONDYS 51) is approved for use in the USA. This targets the exon 51 mutation, so is only suitable for patients whose DMD is caused by this mutation (around 14% of DMD patients). 

AMONDYS 45, an exon skipping treatment targeting exon 45, has also recently been approved for use in the USA. Around 8% of DMD patients have this form of mutation.

These treatments are not currently approved for use in the UK.  

Clinical trials for other exon skipping treatments are currently underway. You can read more about this here.

What would the potential impact of PepGen’s EDO treatment be on DMD patients?  

If shown to be effective in human trials, PepGen’s EDO could be prescribed to patients who have a confirmed mutation in the dystrophin gene that can be treated be skipping exon 51.