Neuro-muscular diseases, Muscular dystrophies, Parkinson’s disease, Autism, Cerebral Palsy and mentally challenged children

The dystrophin protein is essential for the function of muscles. Muscle fibers stretch and contract with great force when a muscle is used. Dystrophin acts as a spring and a shock absorber between the muscle fiber surface and its internal motor made up of a protein called actin. In DMD, due to a mutation in the dystrophin gene, dystrophin is missing and as the actin motor causes the muscle to contract it damages the muscle 0 fiber’s surface membrane because the force-absorbing protection of dystrophin is missing. In small children with DMD, the force of muscle contraction is weak, so there is not much damage and repair can stay ahead of muscle damage. As children with DMD grow, their muscle strength increases and, eventually, muscle damage cannot be adequately repaired. Permanent muscle damage becomes more and more widespread and eventually becomes life threatening as the vital muscles for breathing (diaphragm) and the blood circulation (heart) are affected. Duchenne Muscular Dystrophy (DMD) is one of the most common fatal genetic disorders to affect children around the world.

The gene that encodes the information for the production of the dystrophin protein is the largest gene in the human body, containing 2.4 million base pairs of genetic information. DMD is caused by mutation of the dystrophin gene that prevents the production of dystrophin protein. The most common defects in the dystrophin gene leading to DMD are deletions, or missing pieces of DNA needed to properly direct the production of dystrophin. More specifically, the genetic mutations leading to DMD arise when a fragment of DNA is lost at a point in the gene that severely disrupts correct translation of the genetic information needed to direct dystrophin production.

Sometimes there is a less severe mutation that causes the loss of a small fragment of DNA at a point in the gene where the remaining information is not ruined and the cell has sufficient information to make a truncated, but still functional, form of dystrophin. In this case, although the dystrophin protein is smaller than dystrophin produced from the instructions of a whole gene, it can still perform some of the shock-absorbing tasks of dystrophin. Mutations leading to a shorter but functional dystrophin protein are seen in the milder, Becker form, of muscular dystrophy (BMD).Watch Full Movie Online Streaming Online and Download

Exon Skipping

Several years ago scientists identified a way to potentially restore the functionality of a gene containing a mutation resulting in DMD by a process called exon skipping. Through exon skipping it may be possible to realign the translation of genetic information in the dystrophin gene and promote synthesis of a shortened, but functional, version of the protein. We are developing exon skipping drug candidates with this potential. If these drugs are successful the course of DMD could be slowed down and the severity of the muscle disease could be reduced.

The relationship between exon skipping and the DMD deletions is shown below for some of the more frequent deletions in DMD. The deletions shown in the table are such that skipping of a single exon could be expected to repair the RNA and benefit the patients. There are also deletions  (not shown) that require skipping of more than one exon and therefore need more than one drug to be beneficial.