Pre-Clinical Portfolio
Prosensa’s proprietary technology platform, correcting mutated mRNA in life threatening disorders, may be applicable to a wide variety of diseases. Prosensa has achieved first clinical proof of concept in Duchenne Muscular Dystroph, and has now also initiated (pre)clinical programs for the development of antisense products for other indications including Myotonic Dystrophy and Huntington’s Disease.
| Indication | Compound | Discovery | Pre-clinical | Phase I/II | Phase III |
|---|---|---|---|---|---|
| Duchenne Muscular Dystrophy (DMD) | PRO045 | ||||
| PRO053 | |||||
| PRO052 | |||||
| PRO055 | |||||
| Myotonic Dystrophy (DM1) | PRO135 | ||||
| Huntington's Disease (HD) | PRO289 |
Targeting diseases with unmet medical needs
Prosensa is targeting (rare) diseases with unmet medical needs, in particular neuromuscular disorders for which no effective treatment is yet available. Current treatment is mainly focused at managing the symptoms. The need for a therapy for any of the diseases listed below is therefore unambiguous. Prosensa has a unique proprietary technology platform based on correction of mutated mRNA. In this field Prosensa has achieved first clinical proof of concept in Duchenne Muscular Dystrophy.
Pre-clinical details
Duchenne Muscular Dystrophy (DMD)
The broad mutation spectrum found in DMD will require the development of a series 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.
As DMD is relatively frequent (~1 in 3 500 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 further increases the applicability of this approach.
Prosensa’s most advanced pre-clinical programs focus on exon 45, exon 53, exon 52 and exon 55. It is anticipated that the company will be able to progress the programs that target exons 45 and 53 into the clinic in the first half of 2012.
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 (CUG) 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 in pre-clinical testing. Because of the generic therapeutic approach the same compounds can also be used to treat other CUG trinucleotide repeat expansion diseases (TREDs) such as spinocerebellar ataxia (SCA) and Huntington’s disease - like 2 (HDC2).
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 (CAG) repeats and thus glutamine residues. Prosensa has developed a lead compound that reduces cellular levels 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), such as various spinocerebellar ataxia types and Kennedy’s disease.