Results from the Gensight Biologics Trial of ND4 Allotopic Expression

Gensight Biologics is the company that emerged from the first viable line of allotopic expression research, in part supported some years ago by the SENS Research Foundation and the charitable donations of our community. Allotopic expression is the name given to gene therapy to copy mitochondrial genes into the cell nucleus, providing a backup source of proteins. Since mitochondrial DNA damage resulting in loss of function for genes involved in packaging energy store molecules is one of the causes of aging, allotopic expression of all thirteen genes used in this process will remove this contribution to degenerative aging and age-related disease. This is challenging work and still in progress - only three of these genes have had allotopic expression demonstrated to date. Along the way, however, these incremental successes can be used to cure inherited mitochondrial disorders caused by the loss of one specific mitochondrial gene, such as the blindness of Leber's Hereditary Optic Neuropathy. That is the initial goal for the Gensight Biologics staff. They are well funded these days, having gone public earlier this year, and are making good progress, as this latest trial data shows. Their GS010 product is the vector for introducing suitably modified ND4 into the cell nucleus:

GenSight Biologics, a biopharma company that discovers and develops innovative gene therapies for neurodegenerative retinal diseases and diseases of the central nervous system, today reported additional promising results after 78 weeks of follow-up in its Phase I/II clinical trial. These results confirm the favorable safety and tolerability profile of GS010, while demonstrating sustainable visual acuity improvement in patients with Leber's Hereditary Optic Neuropathy (LHON). Each cohort of three patients was administered an increasing dose of GS010 through a single intravitreal injection in the eye most severely affected by the disease. Recruitment was completed in April 2015 and long-term follow-up is ongoing. These patients had an average onset of disease of 6 years at the time of treatment. At baseline, both treated and untreated eyes had an off-chart median visual acuity.

At 78 weeks post-injection, the mean change of visual acuity from baseline in the treated eyes of all patients* was -0.61 LogMAR, equivalent to a mean improvement of +30 ETDRS letters. For all untreated eyes at week 78, the mean change from baseline was -0.31 LogMAR, equivalent to a mean improvement of +15 ETDRS letters. This provides a treatment effect (mean difference between treated worse-seeing and untreated best-seeing eyes) of +15 letters in favor of treated worse-seeing eyes. More interestingly, in patients with an onset of vision loss of less than 2 years at the time of treatment, a mean gain of +32 ETDRS letters (-0.63 LogMAR) was observed in treated eyes, while a mean gain of +12 ETDRS letters (-0.23 LogMAR) was observed in untreated eyes, resulting in a difference of 20 ETDRS letters in favor of treated eyes. The patient group with vision loss for 2 years or less at the time of injection demonstrated a treatment effect in favor of the treated eye of increasing magnitude from week 36 onwards.



I saw a recent paper stating that the MtDNA was in fact a lot more content rich than what was previously though.
Aside from the dozen or so genes, that SENS hope to copy to the nucleus, there were apparently dozens of peptide coding genes wrapped into the MtDNA like russian dolls.

I thought Allotopic expression seemed fairly settled but that made me less certain.

Posted by: Arren Brandt at December 28th, 2016 2:02 PM

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