Research News

Drug being investigated for treatment of Duchenne Muscular
Dystrophy

PTC 124 is a novel, orally administered, small molecule, investigational new drug for the treatment of genetic disorders resulting from nonsense mutations. Approximately 15% of boys with Duchenne Muscular dystrophy have the condition due to a nonsense mutation. For these boys alleviation of their symptoms through PTC124 is very real possibility. For more information about PTC124 visit http://www.ptcbio.com

ORICO

The media release by Orico in November 2007 regarding its muscle therapeutic development programme is exciting and offers hope. There is a lot of work (and therefore time) required until the completion of the programme. The work includes toxicity studies in animals, which begin this year, followed by clinical trials in humans. The clinical trials will involve both healthy volunteers and volunteers with neuromuscular conditions.

The MDA of NZ and Orico are collaborating over the possibility of New Zealanders with neuromuscular conditions taking part in any of the phases of ensuing clinical trials. We will keep our membership informed of Orico’s progress through emails, newsletters, our quarterly magazine in touch and direct communications.

The following information is from Orico’s website www.orico.co.nz

Orico has two classes of peptides that efficiently antagonize myostatin (GDF8). The development program is focused develop therapeutics for wound healing and muscle wasting conditions such as sarcopenia, cachexia and other myopathies.
Muscular dystrophies are a group of over 30 genetic diseases, the most prevalent of which is Duchenne Muscular Dystrophy (DMD), characterized by the progressive degeneration of muscle. Currently there are no effective therapeutics for the treatment of MD on the market. Orico's leads have been tested in mouse mdx models and resulted in an almost complete reversal of symptoms in muscles as assessed by histology to detect gross symptoms and biochemical and molecular markers associated with proliferation and differentiation of muscle cells.

First Successful Clinical Study with RNA-based Therapeutic PRO051 in Duchenne Muscular Dystrophy

With the support of the AFM through Téléthon donations, the first ever phase I clinical trial (for feasibility and tolerance) based on the exon-skipping technique has been successfully carried out on children affected with Duchenne myopathy in the Netherlands. Conducted by the biotechnology company Prosensa in collaboration with the Leiden University Medical Centre, this trial used antisense oligonucleotides – small pieces of laboratory-synthesised DNA – placed on the pre-messenger RNA during its conversion to messenger RNA. Thus placed, the genetic mutation is shielded in the messenger RNA so as to allow production of the missing protein.
These results were published in the New England Journal of Medicine.

Duchenne muscular dystrophy is a genetic disease that affects nearly one in 3500 boys at birth. It is linked to a deficit in dystrophin, a protein found under the cell membrane of muscle fibres. Coded by the DMD gene, this protein participates in the stability of muscle fibres when they are subjected to stress. Due to a mutation on the DMD gene, the dystrophin protein is missing. Thus it is impossible for the muscle fibre to resist forces exerted on it during contraction, leading to the progressive degeneration of the boy’s muscles.

In this trial four children aged from 10 to 13 years received a single injection into a leg muscle of an antisense oligonucleotide-based treatment (called PRO051) developed by Dutch researchers led by Judith van Deutekom and Gertjan van Ommen at Leiden University Medical Centre. These antisense oligonucleotides allow exon 51 to be skipped. In other words, they intervene at the moment of passage from pre-messenger RNA to messenger RNA (cf attached computer graphic) to skip the part of the gene containing the mutation responsible for the disease – exon 51 – and thus obtain the production of a shorter protein (called “quasi-dystrophin”). Four weeks after this injection the biopsy results from these patients showed the presence of dystrophin at a significant level of expression, which seems a clinically-promising result.

This is the first time ever that exon-skipping in a muscle of Duchenne myopathy patients and using a totally new therapy based on RNA has been obtained. A phase I/II trial is already being prepared to test the safety of the treatment but no longer using (local) intramuscular, but subcutaneous administration, thus allowing distribution of the treatment throughout the body.

Exon-skipping can be performed using different tools, and several research teams including that led by Steve Wilton of the Australian Neuromuscular Research Institute are exploring this therapeutic lead to cure genetic diseases.