5 million Euros these days is serious money in RNAi Therapeutics. Last week, Irish biotechnology company Genable Technologies announced that it succeeded in raising such funds for its pre-clinical DNA-directed RNAi Therapeutics-Gene Replacement combo for the treatment of rhodopsin-linked autosomal dominant retinitis pigmentosa (RHO-adRP), an inherited retinal degenerative condition leading to blindness.
To see it flow into DNA-directed RNAi Therapeutics at that makes it particularly noteworthy. It illustrates that ddRNAi is somewhat uncoupled from the current depression in the synthetic RNAi Therapeutics arena due to some technical differences which make it in many ways more similar to traditional gene therapy. Gene therapy, of course, is experiencing a revival, fueled by more and more clinical validation. Incidentally, it which follows a similar boom-bust cycle as RNAi Therapeutics is going through now.
One of the great benefits of ddRNAi Therapeutics is that it can be combined with other DNA-directed modalities, especially the co-expression of protein-encoding genes from the same DNA template. As such, it is particularly amenable to treat autosomal dominant-negative diseases in which the affected gene is important for cellular function thereby precluding approaches that eliminate both the mutated and the healthy copies of a gene. Accordingly, one could use a single DNA molecule from which to direct the suppression of endogenous versions of the affected gene (wildtype and mutant forms) and then replace gene function by providing a version of the gene that is immune to the RNAi.
In Genable’s case, AAV vector capacity limitations meant that a mix of two AAV vectors had to be co-administered by subretinal injection, one carrying the ‘immunized’ rhodopsin gene, the other the shRNA against the endogeneous rhodopsin copies. This apparently did not affect much treatment efficacy. Indeed, it was argued that the co-administration approach would actually increase dosing flexibility by being able to adjust the amount of each component independently. On the other hand, it is possible that the use of vectors with larger capacities, such as the lentiviral system that Oxford Biomedica and Sanofi-Aventis are busy exploring for ocular gene therapy, may have its advantages here. Importantly, it was shown that therapeutic efficacy in the retinitis pigmentosa animal models strictly depended on the presence of both gene replacement and gene knockdown components.
Although the concern with causing harm by knocking down the wild-type allele is often only a theoretical one, as is for example the case with Huntington’s Disease (HD), and depends on the degree of knockdown, other applications for which this approach holds promise are sickle cell anemia, alpha-1 antitrypsin, pachyonychia congenita (PC), amonst many others.
The PC project by TransDerm and collaborators is a good example in the RNAi Therapeutics space for the challenges faced by the alternative approach to treating such autosomal dominant diseases, namely by specifically directing the drug candidate towards the mutated gene/gene product so as to leave the wild-type copy untouched. The problem here is that because the potential mutations can be broadly distributed over a gene, restricting a therapeutic to targeting only one such genetic lesion (or associated gene polymorphisms) can dramatically reduce the number of patients eligible for such a targeted therapeutic. This also explains why the first clinical trial by TransDerm was a placebo-controlled, split-body dose-escalation trial in a single patient (!) as there may not be more than a handful of known patients in the world with the applicable mutation.
The 5 million Euros will be used to bring Genable’s lead candidate, GT038, into clinical development. RHO-adRP seems like a good ddRNAi application as even the correction of only a fraction, e.g. 1/3 to 1/2 of the affected photoreceptors, may be enough to support vision. It is good to finally see a number of ddRNAi Therapeutics candidates based on sound pre-clinical data move into the clinic.
(For another promising late preclinical candidate, see Calimmune's HIV approach)