Calpains represent a family of calcium-dependent, soluble, neutral cysteine proteases, which have been shown to play major roles in a number of physiological and pathological conditions. The major and ubiquitous members of this family are calpain-1 and calpain-2 (aka µ-calpain and m-calpain), which have been the object of the majority of publications in the calpain literature. While calpains have been implicated in both synaptic plasticity, as well as in neurodegeneration, there has been a paucity of studies attempting to delineate the respective functions of calpain-1 and calpain-2 in these phenomena. Likewise, generic calpain inhibitors and their use to treat diseases have been unsuccessful as therapeutics.
Work in the Baudry's laboratory over the last 5 years has provided a major breakthrough in the field by demonstrating that calpain-1 and calpain-2 play opposite functions in both synaptic plasticity and neuroprotection/neurodegeneration. Thus, while calpain-1 activation is required for initiating synaptic plasticity and learning and memory, calpain-2 activation during the consolidation period limits the extent of plasticity and learning and memory. On the other hand, calpain-1 activation is neuroprotective, while calpain-2 activation is neurodegenerative. These findings have major implications for the development of new therapeutic approaches for disorders associated with learning and memory impairment as well as neurodegeneration. Accordingly, a selective calpain-2 inhibitor could enhance learning and memory and be neuroprotective. Likewise, a selective calpain-1 activator could have similar properties. These predictions have been confirmed experimentally in mouse models of learning impairment and of neurodegeneration. In particular, a selective calpain-2 inhibitor, NA101, was identified and found to be a potent learning enhancer at low doses as well as neuroprotective in mouse models of acute glaucoma and traumatic brain injury (at a dose of 0.3 mg/kg, ip injection 1 h after the insult). These findings were recently reviewed in a high-impact journal, Trends in Neurosciences: Calpain-1 and calpain-2: the yin and yang of synaptic plasticity and neurodegeneration (dx.doi.org).
Selective calpain-2 inhibitors are expected to be used effectively for treatments of diseases related to synaptic dysfunction, synaptic degeneration, and neurodegeneration, including idiotypic and familial forms of Alzheimer's disease and Parkinson's disease, and dementia, Huntington's disease, Amyotropic Lateral Sclerosis (ALS), seizure, encephalitis, stroke, vasospasm, hypovolemic shock, traumatic shock, traumatic brain injury, reperfusion injury, multiple sclerosis, AIDS related dementia, neurotoxicity, head trauma, and spinal cord injury, glaucoma, open-angle glaucoma, angle-closure glaucoma, normal tension glaucoma, congenital glaucoma, pigmentary glaucoma, pseudoexfoliative glaucoma, traumatic glaucoma, neovascular glaucoma, irido corneal endothelial syndrome, ischemia in the eye, ischemia in the retina.
They could also be useful to effectively to treat diseases of synaptic and behavioral dysfunction, which include but are not limited to Schizophrenia, Autism Spectral Disorders, Bipolar Illness, drug-induced psychosis, Post-Traumatic Stress Disorder (PTSD), depression and suicidal thoughts, phobias, obsessive-compulsive disorder, trisomy 21, ADHD, and ADD. Autism Spectral Disorder includes Autistic disorder, (classic autism), Angelman Syndrome, Asperger's disorder (Asperger syndrome), Pervasive developmental disorder not otherwise specified (PDD-NOS), Rett's disorder (Rett syndrome), Childhood disintegrative disorder (CDD).
It is important to stress that, as of today, there is only one Phase I clinical trial initiated by Abbvie for testing the effects of a non-selective calpain inhibitor (clinicaltrials.gov). Based on our experience with calpain-1 KO mice, we predict that this inhibitor will fail, as blocking calpain-1 exacerbates the neurodegenerative effects of calpain-2 activation.
There is also an abundant literature linking calpain-2 to a variety of non-neuronal indications, including cancer and diabetic neuropathy, and we will explore how to expand the applications of our selective calpain-2 inhibitors in these other fields.
One of NeurAegis molecule bound to its target
As a global company committed to improving the lives of people around the world with innovative and effective medicines, NeurAegis is joining the global effort to ease the burden of Traumatic Brain Injury (TBI).
Examples of mouse brains 3 days after TBI. On the left, 2 animals treated with vehicle. On the right, 2 animals treated with NA101 1 h after the insult.
Stroke is a similarly difficult condition for patients and their loved ones. NeurAegis is exploring ways to treat stroke patients as early as possible after the brain attack, in order to protect as many neurons as possible.
Computational design of NeurAegis molecules.
By being committed to neuroprotection, NeurAegis aims to continue to make a significant and positive difference in the lives of patients.
To learn more about the progress of NeurAegis' clinical development projects, visit the Overview of R&D Pipeline on the NeurAegis Pharma Inc. Web site.