Neuropath Therapeutics, a start-up company based in Wuhan Optics Valley Biological City, China, has announced a Series A funding round on April 8th for €16.9M (CNY [Chinese Yuan] 130 million), led by Fosun and Sequoia Capital China. The company is aiming to develop a gene therapy treatment for Leber’s hereditary optic neuropathy (LHON), a maternally inherited disease resulting in simultaneous or sequential bilateral visual loss. Neuropath’s research work on LHON was developed by Prof. Bin Li’s at Wuhan Tongji Hospital, who previously authored a Nature article in 2016 to evaluate the efficacy and safety of a recombinant adeno-associated virus 2 (AAV2) carrying ND4 (rAAV2-ND4) treatment for LHON. Neuropath’s investment funds will be used to advance translational research and GMP manufacturing facility for both LHON and other based gene therapy products for inherited retinal degenerations.
While gene therapy research has made enormous progress in recent years targeting a broad range of dominant and recessive disorders, relatively less attention has been focused on gene disorders associated with the mitochondrial genome. Targeting highly differentiated neuronal cells has been more than challenging and so the prospect of specifically targeting a sub-cellular organelle has seemed only a remote possibility at best. To date researchers have characterized in excess of 200 mitochondrial genome mutations that are associated with a broad range of human disorders, many of which are fatal. Among ophthalmic disorders, research dating back to 1988 indicated a connection between LHON and mtDNA when studies reported a homoplasmic nucleotide transition from guanosine to adenosine at position 11778 resulting in an arginine-to-histidine substitution in ubiquinone oxidoreductase (NADH) subunit 4 (ND4) of mitochondrial complex I. It is now known that the majority of LHON cases are associated with mutations in one of three mitochondrial genes that encode subunits of the same complex I of the mitochondrial respiratory chain. This complex I enzyme, containing 7 subunits encoded by mtDNA, is closely associated with the inner mitochondrial membrane, while a further 35 subunits, encoded by nuclear DNA, are imported into the organelle to facilitate specific steps of the respiratory pathway. Mitochondrial ND4 can only be translated inside the mitochondria (rather than on cytoplasmic ribosomes) as the TGA codon at amino acid 16 of the gene is read as tryptophan in the mitochondria but as a stop codon by the nuclear genetic code.
An estimated 50% of LHON patients harbour the G11778A mutation and as such, represent a significant patient population addressable with an ND4 gene therapy approach. Neuropath’s work has now reported that Professor Bin Li has conducted a second international clinical trial in 159 patients with LHON, following their 2016 Nature article. According to the company, preliminary safety and efficacy data from the 12th month of the trials were similar to the first clinical trial, with no safety concerns, thus “demonstrating that AAV2-ND4 gene therapy is a promising treatment for LHON.” Elsewhere the first clinical trials were led by institutions in the EU region and the United States.