Duchenne muscular dystrophy (DMD) is a rare condition that is typically treated with the help of steroids, to manage symptoms, as scientists are yet to close in on a cure. However, the first-ever gene therapy for the disease is set to open doors for further therapeutic research. As we observe World Duchenne Awareness Day on September 7, let us take a look at the recent progress that’s been made in the field.

Estimated to affect one in nearly every 5000 children, most of them assigned male at birth (AMAB), Duchenne muscular dystrophy leads to muscle weakness. Infants diagnosed with the disease often find it hard to climb stairs, run and jump, with symptoms that tend to get progressively worse. The disease is also linked to cardiomyopathy – a debilitating condition that affects the heart muscle, making it difficult for the heart to pump blood, and could result in heart failure – breathing issues, and developmental delay.

The disease is caused by a gene mutation, one that results in a protein called dystrophin – which is needed for muscle cells to thrive – no longer being produced, and, because of which, the muscle cells die. Being an X-linked disorder – meaning that the dystrophin gene mutation lies on the X chromosome – children AMAB who have the mutation, will be affected by the disease. Whereas, because children assigned female at birth (AFAB) have two X chromosomes, if only one of the two chromosomes has the mutation, they will be carriers, since DMD is a recessive condition – where both the chromosomes must have the faulty genes. Still, 30% of cases happen spontaneously, and are not inherited.

Can gene therapy save DMD patients’ lives?

U.S.-based Sarepta Therapeutics’ ELEVIDYS aims to target the root cause of DMD, the genetic mutation. By delivering a gene that codes for an alternative form of dystrophin, known as ELEVIDYS micro-dystrophin, muscle cells can continue to develop normally. To ensure that the gene is safely delivered to the cells, the genetic material is packaged in an adeno-associated virus (AAV) vector – a popular vector used in gene delivery – and transported. 

Its success in clinical trials led the U.S. Food and Drug Administration (FDA) to back the drug, for patients with DMD who are still able to walk around (ambulatory patients), in June. Two studies found the drug efficacious, while adverse reactions like fever, nausea and low blood platelet count were observed. Although it can be administered to those with the dystrophin genetic mutation, it cannot be given to patients with DMD who have a missing gene.

“Duchenne is a relentlessly progressive, degenerative disease, robbing children of muscle function,” said Jerry Mendell, pediatric neurologist and principal investigator at the Center for Gene Therapy at Nationwide Children’s Hospital. “The increases in ELEVIDYS dystrophin expression and the functional results that we see can make a difference in the lives of our patients.”

A confirmatory trial is yet to see fruitful results, which is set to be announced by the end of the year, explained Doug Ingram, president and chief executive officer of Sarepta Therapeutics, in a press release.

“The approval of ELEVIDYS is a watershed moment for the treatment of Duchenne. ELEVIDYS is the first and only gene therapy approved for Duchenne, and this approval brings us closer to our goal of bringing forward a treatment that provides the potential to alter the trajectory of this degenerative disease,” said Ingram. “As we prepare to launch ELEVIDYS, we should acknowledge and celebrate the decades of dedication and work from the patient community, families, clinicians, and our Sarepta colleagues that resulted in today’s approval.”

A cure in the making?

Moreover, in a string of welcoming news, UC Davis Health in the U.S. is also ramping up gene therapy research, but this time around, in hopes for a cure. In an attempt to thwart the mutation, scientists are developing a gene editing therapy that could allow pregnant people to give birth to children who are free from the disease. Their technology, Cure DMD, is being designed to edit the dystrophin-coding genes in the heart, diaphragm and limb muscles of the fetus, and correct the mutations. The therapy, which will be carried by a lipid nanoparticle – a non-viral method of delivery –  will be given as an in-utero injection. Since gene editing is typically a permanent fix, if done right, it could prevent the disease from occuring altogether, according to Aijun Wang, researcher and professor at UC Davis. 

Now, researchers at the university look ahead as they test the safety of the therapy on mice models as well as cells obtained from patients with DMD.

Pioneering therapy deemed a breakthrough

More recently, NS Pharma, headquartered in New Jersey in the U.S., was granted the Breakthrough Therapy Designation by the FDA – an approval that’s given to drugs that treat life-threatening conditions – for its investigational drug. This came after the drug candidate’s first-in-human trials that were held in Japan, drew attention. The drug NS-065/NCNP-01, is an antisense nucleotide that follows a mechanism called exon skipping. 

In the case of Duchenne muscular dystrophy, the mutation is often due to missing patches of the dystrophin-coding gene. These patches are the bits that code for proteins, known as exons. When an exon gets deleted, this breaks the continuity of the chain of exons in the gene. This is where exon therapy can come to the aid. By directing an antisense nucleotide – which is a small DNA fragment – like NS Pharma’s drug, to the region that’s been disconnected, it can help mask the exon that needs to be skipped, in order for the rest of the gene to be pieced back together. 

Applying this mechanism to almost all of its DMD drug candidates – most of which are in preclinical stages – NS Pharma is set to begin phase two trials NS-065/NCNP-01 in the U.S. and Japan – the latter one conducted by its parent company Nippon Shinyaku – and only time will tell how it will fare. 

DMD research: past trials and tribulations

However, this series of DMD drug breakthroughs is fairly recent. With multinational pharmaceuticals Pfizer and Roche having abandoned their myostatin inhibitor drug candidates, and American biopharma FibroGen’s monoclonal antibody pamrevlumab failing to climb DMD clinical trials, clinical woes have limited the treatment options for the condition.

And, while steroid therapy is regarded as the only standard of care, which contradictorily, leads to side effects like muscle weakness, there is a drought of DMD treatment approaches.

Yiannis Kiachopoulos, CEO and co-founder of Causaly, an artificial intelligence (AI)-based drug discovery platform explained that this is because DMD, which is a rare disease, impacts a much smaller population compared to many other diseases, making drug discovery specifically challenging.

“When there’s a smaller pool of candidates with muscular dystrophy, it can complicate the development of targeted therapies and subsequent clinical trials. Not to mention, it’s an expensive process: on average, it takes upwards of twelve years and $2 billion for every drug that reaches the market, and both factors only increase for rare diseases that have few solutions,” said Kiachopoulos.

AI: a drug discovery tool to tackle rare disease research challenges

But AI could help bypass these challenges by lending a hand to researchers looking to identify new biomarkers to predict treatment responses, according to Kiachopoulos. A task that can take months and years, can be performed almost instantly, through machine learning.  

“Scientists have been relying on antiquated research methods for decades, depending on manual searches through databases to find related research and historical data,” said Kiachopoulos. “This process takes a long time, and it can also lead to research bias, or relying on specific material that might seem to be the most relevant information, but they can often be missing vital research that is better suited for their cause. For example, using PubMed to search ‘biomarker Duchenne Muscular Dystrophy’ revealed over 800 documents across 87 pages, which could take weeks to read.” 

Kiachopoulos revealed that more than 500 biomarkers of DMD were identified shortly after running the data on its AI platform. Moreover, this was propped up by around 2500 studies, unlike the ‘biomarker Duchenne Muscular Dystrophy’ search on PubMed that was mentioned by Kiachopoulos, who pointed out the bias in conventional keywording.

“Research bias can translate into failed preclinical and post clinical phases, forcing everyone back to the drawing board to start over,” said Kiachopoulos. 

“When scientists have the best information in front of them, they are able to build hypotheses that are more likely to be successful in the next phase of testing – which could mean expanded solutions for DMD and less money spent on failed trials… This is vital for rare diseases from muscular dystrophy to Huntington’s disease to cystic fibrosis, where current solutions are minimal, and expectant patients are hoping for more options in the near future.”

With machine learning technology on the rise in healthcare, like how it is stepping up breast cancer diagnosis, it could change the game for DMD research. And with the recent turn of promising events, like in the field of gene therapy, we might finally see fruition of therapeutic research that is long overdue.