A hybrid approach to disease modeling identifies both a gene therapy and diabetes drug with the potential to tackle late-onset retinal degeneration
Geoffrey Potjewyd | | Quick Read
Are we on the precipice of a treatment for late-onset retinal degeneration (L-ORD)? Well, knowledge is power – and researchers from the National Eye Institute (NEI) have developed a hybrid tissue engineering and computer modeling approach to decipher L-ORD pathology. Not content with one win, they also identified two treatment options at opposite ends of the drug development spectrum – a novel gene therapy and the repurposing of a common diabetes drug (metformin).
Led by Kapil Bharti, the team grew retinal pigment epithelium (RPE) from the stem cells of a patient with the genetic mutation in CTRP5 that causes L-ORD. First, they confirmed that the patient RPE model expressed low amounts CTRP5 protein, which their computer model identified as less likely to bind and inhibit AMPK signaling. Second, they used the patient RPE model to test and prove that inhibition of AMPK signaling reduces L-ORD pathology – a target in the crosshairs. “This hybrid approach has huge potential, because it allows us to test molecular simulations as actual experiments in patient cells,” says Bharti. “But this is limited to a small number of cases where the molecular structure of the protein under investigation is known. Our key advantage here was the ability to use patient eye (RPE) cells made from their stem cells.”
The findings led to assess the potential of a gene therapy to inhibit AMPK signalling via CTRP5 overexpression and the use of metformin to modulate AMPK activity – both worked but which avenue to take forward? “Gene therapy trials may take time to set up because it requires extensive preclinical work upfront demonstrating safety of gene therapy constructs manufactured under clinical settings,” Bharti explains. “Because of the complexity and significant cost associated with gene and cell therapies, we chose to also test metformin, which has decades of clinical use history. In fact, metformin trials are already being planned by our colleagues and the NEI will soon be announcing an oral metformin-based trial for L-ORD. Stay tuned.”
Instead of spending years in drug development pipelines, should we focus more effort on seeking approved drugs with decades of real world data? “Drug repurposing has been under-appreciated,” says Bharti. “It has benefits, not least the ability to get the drug to patients much faster. Metformin is an excellent example. Its anti-senolytic properties can be leveraged for several retinal degenerative diseases. L-ORD is the example we published, but we have a similar in vitro (using patient cells) and in vivo (in an animal model) studies ongoing for another childhood onset retinal degenerative disease called Stargardt disease – along with an NEI clinical trial already taking place with oral metformin for Stargardt patients.”
- KJ Mayagishima et al., Commun Biol, 4, 1360 (2021). PMID: 34887495.