A More Serious Trial Failure for Gensight's Allotopic Expression Implementation

Gensight Biologics uses allotopic expression of a mitochondrial gene, ND4, to attempt to treat the inherited blindness condition Leber hereditary optic neuropathy, in which this gene is mutated and dysfunctional. An altered copy of ND4 is introduced into the cell nucleus, and the protein produced is delivered back to the mitochondria where it is needed for correct function. A fairly standard gene therapy is used to deliver this payload into the retina. Unfortunately, after promising results from earlier trials and technology demonstrations, their late stage trials are failing.

It remains to be seen as to why this is the case. Earlier work makes it clear that the technology works in principle. It is possible that intervening too late cannot clear out enough of the damage already done, and that damage makes further decline inevitable, or recovery difficulty. This is a systemic problem for many conditions, given the way in which the structure and enormous cost of clinical trial regulation pushes companies towards the late stage of the disease, rather than earlier, preventative treatment. Equally, it may be that this formulation of the allotopic expression gene therapy isn't achieving a great enough coverage of retinal cells to produce reliable benefits. There are many possible reasons for failure.

A phase 3 trial of GenSight Biologics' Leber hereditary optic neuropathy (LHON) gene therapy has missed its primary endpoint. The AAV gene therapy was no better than placebo at improving vision at 48 weeks, leading GenSight to look to future updates to salvage the study. GenSight designed GS010 to improve the vision of patients with a particular mutation in the mitochondrial ND4 gene and moved the gene therapy into a pair of phase 3 trials in 2016. One trial enrolled patients who had suffered vision loss for 6 to 12 months. The other recruited people whose vision loss began less than six months ago. Both trials missed their primary endpoints.

The latest clinical setback involves LHON patients with six months or less of vision loss enrolled in the RESCUE trial. As in the other study, GenSight set out to link GS010 to a 15-letter improvement over placebo on a vision test. Each subject received GS010 in one eye and a sham injection in the other. This time around, the eyes treated with GS010 deteriorated by 19 letters over the first 48 weeks of the trial, compared to a 20-letter decline in the control cohort. The top-line figures hide a trend that shows vision in both arms of the trial declined before improving. Eyes treated with GS010 improved by 13 letters from their low point, while the placebo group recorded an 11-point improvement.

The trial failed to show GS010 is statistically superior to placebo against secondary endpoints, too. After 48 weeks, GS010 statistically had no more effect on the temporal retinal nerve fiber layer, papillomacular bundle thickness and ganglion cell volume than placebo. While GS010 outperformed the sham treatment on some other measures, the overall data set offers little encouragement that the gene therapy is effective at 48 weeks. The question is whether it will become effective as more weeks pass. GenSight thinks it will, in part because of its experience with the other phase 3 trial.

Link: https://www.fiercebiotech.com/biotech/gensight-s-vision-loss-gene-therapy-again-fails-phase-3


It is a disappointing result. But ultimately if we can print/regenerate/transplant retina and optical nerves it would be a did for many conditions with different underlying reasons.

This is a setback for the gender therapy field in general but it gives valuable experience for each the investors paid a lot...

Posted by: Cuberat at February 28th, 2019 7:37 AM

Small molecule drugs will be the way forward for anti-aging therapies for the next few decades at least imo.

Posted by: aa3 at February 28th, 2019 4:26 PM

Well that's a shame. I've taken a deeper look at this, with https://academic.oup.com/brain/article/128/1/35/524240 as a resource. Here's my take, where I will keep in mind some potential bias in favour of the company:

The first thing to remember, is that the current trial with no visible benefit was set in patients who have had the pathology for 6- months, instead of the older trial with bilateral benefits, where the pathology existed for 6-12 months. Therefore, this trial is looking at an early stage of the disease, as the company have said.

Second, how would replacing the diseased gene have an impact on the disease late, rather than early? I can only think of two factors which would have this make sense. 1) Survivorship bias (on the cellular level) and 2) A feedback loop of chronic damage

1) In the later stages of the disease, neurons more resistant to the damage accumulated will remain, effectively leaving only the most robust cells in the nerve - those which will take a lot of damage to push over the edge to destruction.

2) Compound this with chronic damage. From what I can tell, the mechanism of cell death in LHON is possibly-ROS-caused axon damage, possibly-inflammation-linked demyelination (with associated bodies of amyloid precursor protein) (keeping in mind that axon damage can cause demyelination in some cases) and possibly some level of autoimmune response which could be linked to that demyelination in some cases.

So, inflammation and axon damage cause demyelination, which causes inflammation (and associated release of ROS from the mitochondria) and a possible autoimmune response, causing axon damage and demyelination. Repeat.

This is my best guess for a "positive scenario" for GenSight, though i'm aware it could be incorrect, and it's easy to let biases invade your logic. Any criticism?

Posted by: Patrick Deane at March 5th, 2019 7:23 PM

See Soto et al. 2022, "Balanced mitochondrial and cytosolic translatomes underlie the biogenesis of human respiratory complexes". They adapted ribosome profiling to the human mitochondria, and detected ribosomal attachment indicating that MT-CO1, MT-CO2, and MT-ND5 all produce alternative translated proteins that extend past the putative stop codon. This is probably due to ribosomal frameshifting. The mitochondrial ribosome descends from bacteria, so its frameshifting triggers will be completely different than that of nuclear ribosomes.

If there's ribosomal frameshifting in ND4 as well, its alternative protein would almost certainly not be translated in the nucleus.

Posted by: Phil Goetz at February 1st, 2023 10:20 AM
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