Unmet NeedAmytrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, and results in muscle atrophy and loss of motor control. ALS affects approximately 17,000 people in the United States and 450,000 worldwide at any given time, and the average life expectancy from diagnosis to mortality is between 2-5 years. Investigation into the pathophysiology of ALS revealed that astrocytes (support cells for neurons) secrete toxic ubiquitin, causing motor neuron degeneration. The toxic molecules are released via gap junctions, which are channels that allow astrocytes to transfer materials between cells. One component of the gap junctions, a connexin known as Cx43, exhibits altered expression in several neurological diseases and is functionally implicated in motor neuron cell death in vitro. However, no ALS treatments currently exist that inhibit the role of Cx43 in mediating astrocyte’s toxicity. Previous studies investigated the use of non-specific gap junction inhibitors, which had a poor safety profile, and peptide blockers, but found that they were too large and could not easily penetrate the blood brain barrier. Hence, there is a need for a Cx43-specific treatment that easily penetrates the blood-brain barrier and inhibits astrocytic involvement in ALS to slow disease progression and improve survival.
Technology DescriptionTonabersat is a novel cis benzopyran derivative molecule that specifically targets and inhibits Cx43. Compared to the non-specific gap junction inhibitors, tonabersat demonstrates better target specificity, thus minimizing the potentially undesirable effects from broad gap junction inhibition. Additionally, unlike large peptide blockers that have difficulty crossing the blood-brain barrier, tonabersat’s small size enables it to easily penetrate the blood-brain barrier to target astroglial cells in the central nervous system. Also, as an orally available compound, tonabersat has an excellent safety profile and is already shown to be well-tolerated in studies for patients with migraine.
In vitro studies have demonstrated that tonabersat can protect motor neurons from astrocyte-induced toxicity, which may slow the process of motor neuron degeneration during ALS’s disease progression.
Stage of DevelopmentThe inventors have performed
in vitro cell culture studies that identified a target (astrocytic Cx43) and demonstrated that inhibition of Cx43 can protect motor neurons from cell death, verifying the viability of the target for ALS treatment. Additionally, further human iPSC co-culture studies demonstrated that tonabersat is neuroprotective for motor neurons in a dose-dependent manner when cultured with astrocytes, indicating its potential as an ALS treatment. The inventors plan to complete ALS modeling studies and hope to perform clinical trials with tonabersat.
