The scientific world is still reeling from the news of the first genome editing of human embryos to treat genetic disease, as we have reported previously here on Epigenie. Unfortunately, the paper suggested that this strategy may need huge improvement or may never be applicable. However, another recently published study, from the laboratory of Juan Carlos Izpisua Belmonte, may represent an exciting step forward in treating some heritable genetic diseases: by stopping their propagation in the germ line before the embryo is even formed.
The group looked at diseases caused by mutations in mitochondrial (mt) DNA, defects that lead to the presence of faulty mitochondria alongside healthy mitochondria within a given cell (heteroplasmy). If the levels of faulty mitochondria remain low, any underlying disease does not usually manifest itself, and so the enterprising researchers sought to find out if they could artificially lower the number of faulty mitochondria by targeting and destroying their DNA in oocytes. Furthermore, they sought to discover if offspring generated from these oocytes also exhibited corrected mitochondrial levels, in effect, stopping the passage of disease from mother to child.
Proof-of-concept experiments used the heteroplasmic NZB/BALB mouse model, which carries two different mitochondrial genomes.
- Using a mitochondrially targeted ApaLI restriction endonuclease specific for BALB mtDNA, the group specifically reduced BALB mtDNA levels in mouse oocytes and 1-cell embryos.
- Importantly, mice born of these embryos still exhibited low BALB mtDNA levels with no ill effects or apparent off-target consequences.
- NZB mitochondria remained unaffected.
- Mitochondrially targeted transcription activator-like effector nucleases (mito-TALENs) specific to the NZB mtDNA also specifically reduced NZB mtDNA in mouse oocytes.
To test the potential use of mito-TALENs in humans, the group generated artificial mammalian oocytes through fusing mouse oocytes with the cells of patients with two different mitochondrial diseases (LHOND and NARP).
- Using specifically designed mito-TALENs the group effectively reduced both LHOND- and NARP-specific mtDNA in separate experiments.
- This may prevent germline transmission of mitochondrial disease, as observed in the mouse model.
This enterprising but simple strategy could represent a safe an effective means to inhibit the transmission of mitochondrially-associated diseases.
Read more on the specifics of this amazing new therapeutic avenue in Cell, April 2015.