Genable is developing gene-based therapies for the treatment of dominantly inherited genetic disorders. This class of incurable disorders comprises hundreds of individual members including different forms of autosomal dominant retinitis pigmentosa (adRP).
Dominant inheritance means that on average 50% of the children of an affected person will be affected by the disorder. Another common feature of these disorders is that the causative genes are often characterised by mutational heterogeneity.
Therefore typically a large number of individual mutations in a single gene can lead to a particular disorder. For example any one of approximately 150 different mutations in the rhodopsin gene (RHO) can lead to adRP. Developing individual therapies for so many RHO mutations is practically impossible.
Genable's technology represents a different therapeutic approach termed suppression and replacement (S&R). The ultimate advantage of S&R is that a single therapy can to treat all of the mutations in a particular gene while still correcting the primary genetic defect; in essence it is mutation independent.
S&R is a dual system working at the messenger RNA (mRNA) level. The suppression component is responsible for eliminating the disease-linked mRNA, which is translated into the mutant protein present in an affected individual and causative of the disorder.
As mentioned above, the suppression component eliminates the target mRNA independent of the particular mutation present in the affected individual. The replacement component supplies an mRNA encoding the wild type (normal) protein.
Notably, the replacement mRNA is refractory to suppression by the suppressor component of the therapy. The principles of S&R do not depend on the actual tools utilised in the suppressor and replacement components and therefore innovation in these tools can be implicated in the future development of S&R.
Genable's S&R approach for RHO-linked adRP employs RNA interference (RNAi), a potent and sequence-specific means of gene suppression. The RNAi suppressor employed for mutant RHO mRNAs recognises a part of the mRNA, which has no sequence variations.
This enables a single RNAi molecule to identify and eliminate any mutant RHO mRNAs; indeed, it also recognises the wild type RHO mRNA. The role of the replacement component is therefore to reintroduce the RHO mRNA in a form, which is suppression resistant but nevertheless provides wild type rhodopsin protein.
This is resolved by introducing subtle modifications in the replacement RHO gene sequence at the RNAi target site. These base substitutions are made using the codon redundancy. This results in a nucleotide sequence significantly different and therefore not recognised for suppression by the RNAi molecule but still coding for the same amino acid sequence and therefore providing the correct protein.
In summary, the combination of S&R eliminates the need to target specific mutations in a wide range of disorders while presenting an effective strategy to overcome the associated pathology. The current suppressor components exploit RNAi to identify and eliminate the mutant mRNA.
The simultaneous delivery of a replacement gene, protected from RNAi suppression through subtle alterations of its nucleotide sequence, provides a replacement protein. In brief, S&R removes the mutant protein by abolishing its mRNA and supplies its normal complement via introduction of a suppression-resistant replacement gene.
GT038 is designed to treat rhodopsin (RHO)-linked autosomal dominant retinitis pigmentosa (adRP).
Retinitis pigmentosa (RP) is a group of inherited degenerations of the retina, the light sensitive layer of the eye. Currently, no approved pharmacological treatment exists for any forms of RP. RHO-linked autosomal dominant retinitis pigmentosa (RHO-adRP) affects a subset of RP patients and leads to clinical blindness in the majority of cases.
Approximately 150 different mutations known to give rise to adRP have been identified in the RHO gene alone. It would be impossible, in terms of either cost or design, to generate separate therapies for each mutation. In addition, simply supplying a normal (wild type) RHO gene will not treat this disease.
The strategy behind the development of GT038 was to design a therapy that is mutation-independent and that will arrest the progression of this debilitating disease. GT038 has undergone successful proof of concept studies in mice. Large animal and first-in-human studies are planned for 2011 and 2013, respectively.