TSHA-104 restored to normal levels elevation of blood lactate on exhaustive exercise in dose-dependent manner in SURF1 knockout mice
TSHA-104 increased COX1 activity in brain and muscle in dose-dependent manner in SURF1 knockout mice
Combination of intrathecal and intravenous delivery did not prove benefit over intrathecal alone
No associated toxicity risks or severe tissue damage were seen
There are no approved treatments for the underlying cause of the disease and the burden of disease and risk of mortality are high
SURF1 deficiency is a monogenic mitochondrial disorder that is the most common cause of cytochrome c oxidase deficient Leigh syndrome, a rapidly progressive neurological disorder that leads to degeneration of the CNS. Leigh syndrome typically presents in the first year of life and is characterized by progressive loss of mental and movement abilities that can result in death in early childhood. Approximately 10-15% of people with Leigh syndrome have a SURF1 mutation, and the estimated prevalence of SURF1 deficiency is 300 to 400 patients in the
“SURF1 is part of cytochrome c oxidase, a mitochondrial enzyme known as COX involved in the metabolic production of ATP. Children with SURF1 deficiency have severely impaired COX activity and cannot generate ATP by aerobic respiration appropriately. This disruption in overall energy metabolism increases anaerobic respiration, leading to elevated levels of lactate and the clinical phenotype of Leigh syndrome,” said
RA Session II, President, Founder and CEO of Taysha, added, “In the mouse model, we are seeing expression of SURF1 in the brain and spinal cord at levels sufficient to effectively restore COX activity in the brain, liver and muscle with one intrathecal administration of TSHA-104. We are encouraged by the ability of TSHA-104 to diminish exhaustive exercise-induced lactic acidosis, supporting intact mitochondrial function under states of stress in these preclinical models. This proof-of-concept study indicates TSHA-104 is safe and effective in rescuing metabolic dysfunction in preclinical models of SURF1 deficiency.”
A one-time intrathecal injection of TSHA-104 resulted in codon-optimized human SURF1 expression in multiple relevant brain and spinal cord regions in SURF1 knockout mice. A combination of intrathecal and intravenous delivery did not provide any benefit over intrathecal delivery alone, supporting continued use of intrathecal administration. TSHA-104 increased mitochondrially encoded cytochrome c oxidase 1 (MT-CO1) abundance four weeks post-injection in the CNS and peripheral tissues and increased COX1 activity in brain and muscle in a dose-dependent manner. Biochemical COX activity correlated with histological COX content level, supporting regional COX activity. Following exhaustive exercise-induced lactic acidosis TSHA-104 was able to rescue elevated lactate levels in SURF1 knockout mice dose-dependently. The safety profile assessed by non-GLP (Good Laboratory Practice) evaluation in wild-type mice using a similar dosing regimen determined no associated toxicity risks or severe tissue damage detected up to one year post-injection. Collectively this proof-of-concept study demonstrates TSHA-104 can safely and sufficiently rescue mitochondrial dysfunction in SURF1 knockout mice, supporting further translational development for the treatment of SURF1-associated Leigh syndrome.
TSHA-104 is an AAV9-based gene replacement therapy encoding the human SURF1 protein that is administered intrathecally for the treatment of SURF1-associated Leigh syndrome. TSHA-104 has been granted Orphan Drug and Rare Pediatric Disease designations by the FDA.
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