Pre-Clinical Portfolio

Duchenne Muscular Dystrophy (DMD)

The broad mutation spectrum found in DMD will require the development of antisense oligonucleotides (AONs) inducing the skipping of a variety of exons. Prosensa’s discovery program is focused on the identification of the most efficient, tolerable, and pharmacokinetically favorable AONs for a series of exons.

As DMD is relatively frequent (~1 in 3 500 affected new born boys) and circa one out of three DMD mutations is de novo, there is a large variety of different mutations. The exon skipping technology is mutation specific because different mutations require skipping of different exons. However, two thirds of all patients carry a deletion of one or more exons, of which 70% cluster between exon 45 and exon 55. Thus, the skipping of specific exons would be applicable to relatively large subpopulations of patients. The majority of deletion mutations (70%) may be restored through the skipping of a single exon. Double exon skipping would be applicable to 8% of deletion patients and increases the applicability of this approach.

Prosensa’s most advanced pre-clinical programs focus on exon 45, exon 53 and exon 52. It is anticipated that the company will be able to progress these programs into the clinic in the coming years.

Myotonic Dystrophy (DM1)

DM1 is the most prevalent muscular dystrophy in adults and is a progressive, degenerative, multisystemic disorder of predominantly skeletal muscle, heart and brain. DM1 is an autosomal dominant disease caused by expansion of an unstable trinucleotide repeat (CTG) in the 3’ untranslated region of the DMPK gene. The increased length of the repeat forms hairpin-like secondary structures and disrupts the normal processing of other RNA transcripts in the nucleus resulting in aberrant cellular function.

The incidence of DM1 is around 1 per 8 000. There is no effective treatment available at present and the congenital form (1 in 20 000 newborns) leads to a life long severe disability and premature death. Prosensa has developed lead compounds that are now used in pre-clinical testing. Because of the generic therapeutic approach the same compounds can also be used to treat other CTG trinucleotide repeat expansion diseases (TREDs) such as spinocerebellar ataxia (SCA).

Spinal Muscular Atrophy (SMA)

Spinal Muscular Atrophy (SMA) is an inheritable lethal disease with an incidence of 1 in every 9,000 newborns. In SMA, patients most often begin to show signs of muscle weakness as infants or toddlers. SMA patients do not have the Survival Motor Neuron (SMN) protein which is critical in motor neurons. In children with SMA, this results in muscle atrophy and weakness, bone and spinal deformities and fatal respiratory complications. Even in milder forms, SMA has a devastating and deadly impact on children. In principle, it is possible to increase SMN protein production by enhancing inclusion of exon 7 in the SMN2 gene transcript. This can be achieved by post-transcriptional modulation of the SMN2 pre-mRNA. Prosensa is developing lead compounds that have shown to be effective in cell models, and which are currently being tested in dedicated SMA mouse models.

Huntington’s Disease (HD)

The causative gene for Huntington's disease, HD, is located on chromosome 4. Huntington's disease is inherited in an autosomal dominant fashion. The prevalence of the disease ranges around 1 per 10000. When the gene has more than 35 CAG trinucleotide repeats, the replication process becomes unstable and the number of repeats can change in successive generations. Because of the progressive increase in length of the repeats, the disease tends to increase in severity and present at an earlier age in successive generations, a process called anticipation. The product of the HD gene is the 348 kDa cytoplasmic protein huntingtin. Huntingtin has a characteristic sequence of fewer than 40 glutamine amino acid residues in the normal form; the mutated huntingtin causing the disease has more than 40 residues. The continuous expression of mutant huntingtin molecules in neuronal cells eventually gives rise to cell death, especially in the frontal lobes and the basal ganglia (mainly in the caudate nucleus). The severity of the disease is generally proportional to the number of extra residues. Prosensa has developed a lead compound that prevents cellular production of aberrantly expanded HTT mRNA and mutant huntingtin protein. It is now further tested in pre-clinical experiments. Because of the generic therapeutic approach the same compound can also be used to treat other CAG Trinucleotide Repeat Expansion Diseases (TREDs).

• Home
• Technology & Products
• Pipeline

Footer navigation

• Contact Us
• Sitemap
• Privacy Policy
• Disclaimer

© 2010 Prosensa Therapeutics B.V.