New hope for patients with Duchenne muscular dystrophy

New hope for Duchenne muscular dystrophy (DMD) patients. A mouse genetic study in PLoS Medicine reports that targeting the P2RX7 gene, a purinoreceptor, may halt the progression of DMD.

Duchenne muscular dystrophy (DMD) is a debilitating and ultimately fatal disease striking roughly twenty thousand new patients - nearly all boys - each year. The disease is caused by a mutation in the dystrophin gene, which leads to the breakdown of skeletal and cardiac muscle, bone weakness, widespread inflammation and in many cases, cognitive and behavioral disorders. There is currently no cure, and symptoms progress from an early age, leaving most patients unable to walk by age 12; the average life expectancy for DMD sufferers is about 25.

Unsurprisingly, research on new treatments for DMD is very active. Many of these research efforts aim to replenish the supply of functional dystrophin to patients' cells via gene therapy or targeted stem cell transplantation - but these strategies come with several difficulties. For one, achieving an adequate level of dystrophin expression in individual cells can be unpredictable - and getting expression in enough cells throughout the entire body to have a significant impact is proving even harder. Also, these therapies generally focus on treating muscle cells specifically, leaving symptoms such as weakened bones, cognitive issues and inflammatory complications untreated.

A new study in PLOS Medicine suggests that a different path may ultimately prove more promising. A number of groups have followed the effects of mutated dystrophin down various molecular pathways, and identified possible targets downstream of dystrophin for treatment. In this paper, a group led by researchers at the University of Portsmouth in the UK and including collaborators in France, Italy, the US, and Russia report preliminary success in targeting the P2RX7 gene, which plays an important role in DMD progression.

The P2RX7 protein is a purinoreceptor, composed of several identical subunits linked together to form ion channels on the cell membrane, which open in response to extracellular ATP (adenosine triphosphate, the chief source of energy in cellular processes). These channels are present on macrophages and other immune cells (muscle cells, among others), and used to detect high levels of extracellular ATP in the body - usually a sign of tissue damage or other critical problems.

But loss of dystrophin function also leads to ATP "leakage" in muscle tissue, where the concentration is already high. This condition leads to a sort of an immune "panic". On muscle cells, P2RX7 pores open wide and cause the cells to undergo autophagy, or triggered cell death. Meanwhile, P2RX7 on macrophages detect the high ATP levels and call in an immune response, increasing inflammation, further damaging the muscle and creating a vicious loop of further tissue breakdown.

The researchers studied the effects of P2RX7 in DMD by utilizing an established mouse model line called mdx, which contains a dystrophin gene mutation and exhibits some symptoms similar to human DMD. They cross-bred these mice with another strain, in which they had knocked out the P2RX7 gene, to produce new mice which had neither functional dystrophin nor P2RX7, and compared those with mice from the original mdx line.

The results were striking! Compared with the mdx mice, those also missing P2RX7 showed improved muscle structure and much lower concomitant inflammation. In physical tests, the mice were also stronger and more coordinated. These effects were observed both in short-term (at four weeks of age) and long-term (twenty months) assays, indicating consistent and lasting changes. Even better, the authors observed significant improvements in non-muscular settings - behavioral and cognitive testing, and assays of bone density loss.

Importantly, the researchers also showed that at least some of the same effects could be achieved using a P2RX7 antagonist. Some of these antagonists are already approved for treatment in other areas, which could be a huge boost for DMD drug development. It's important to note that results in an animal model system do not always translate to humans - but these results are nonetheless very exciting, and represent a possible new "fast track" to much-needed effective treatment of a devastating degenerative disease.