A recent study published in Molecular Therapy shows promise for the long-term efficacy of a novel gene therapy for retinitis pigmentosa (RP) in a canine model.
Give me some background.
As it turns out, RP is a genetically heterogeneous inherited retinal degeneration (IRD) that can arise from a mutation in 69 known genes.
To note, RP due to cyclic nucleotide-gated channel beta 1 (CNGB1) mutations (the target gene) is the sixth most common cause of recessive IRD. Humans and dogs share this particular gene in common.
While RP from CNGB1 mutations causes rod function loss early, retinal structure and rod loss progress slowly. This provides what the study authors call an excellent “window of opportunity for gene augmentation therapy.”
Why a canine model?
CNGB1-RP specifically develops in humans while dogs are afflicted by progressive retinal atrophy (the human equivalent to RP). Further, dogs offer a large animal model with an analogous eye size to humans.
Tell me about this gene therapy.
Because the CNGB1 cDNA is so large, it limits the size of what can be added to the adeno-associated virus (AAV) expression cassette.
The therapeutic vector is an adeno-associated virus serotype 5-with transgene under control of a novel short human rhodopsin promoter (AAV5-RHO-CNGB1) that can be delivered to the subretinal space.
Now the experiment.
By using an AAV vector, investigators delivered a normal version of the CNGB1 gene that was controlled by a novel gene promoter (a modified form of the RHO promoter).
This novel gene promoter guaranteed CNGB1 was active within the rod photoreceptor.
From there, the therapeutic was delivered by subretinal injection to potentially renew retinal tissue function along with possibly reducing the accumulation of toxic amounts of cyclic guanosine monophosphate (cGMP) in normally functioning rods. If cGMP levels are left unchecked, it can lead to rod photoreceptor death.
So what were the results?
The therapy restored rod-mediated retinal function for 12 months following treatment in the CNGB1 mutant dogs.
In-vivo imaging showed long-term preservation of the retinal structure, and testing revealed the formation of a functional copy of CNGB1.
Any adverse effects?
One dog had a mild inflammatory response to the injection, followed by lower subsequent electroretinogram (ERG) amplitudes.
The study authors noted that this result was similar to patients treated with voretigene neparvovec-rzyl (Luxturna), the first approved commercial product based on AAV vectors for IRD.
Take away.
While there are many gene therapies in development for IRDs, including RP, there is currently no cure for RP.
The success of this canine-based study opens pathways for the future clinical development of AAV5-RHO-CNGB1 for the treatment of RP in humans.