science
Pushing the boundaries of neuroscience drug discovery
At IAMA, we are working to unlock major breakthroughs in neuroscience drug discovery and precision medicine to develop personalized treatments for patients suffering from untreatable neurological conditions. We are developing treatments to make a meaningful impact on individuals and families affected by pediatric central nervous system disorders, including autism and epilepsies.
We are identifying and advancing diverse classes of small molecules to selectively inhibit clinically validated targets, including the sodium-potassium chloride cotransporter (NKCC1).
our approach
Targeting the master regulators of multiple CNS diseases
A signaling imbalance between excitation and inhibition in the brain causes some epilepsies and forms of autism.
NKCC1 is a member of the Cation Chloride Cotransporter family, which mediate chloride transport across the membrane.
Cation-coupled chloride cotransporters (CCCs) modulate the transport of sodium and/or potassium cations coupled with chloride anions across the cell membrane. CCCs thus help regulate intracellular ionic concentration and consequent cell volume homeostasis. This has been largely exploited to develop diuretic drugs that act on CCCs expressed in the kidneys. However, a growing wealth of evidence has demonstrated that CCCs are also critically involved in a great variety of other pathologies, motivating the most recent drug discovery programs targeting CCCs.
The role of NKCC1 is to mediate the coupled movement of chloride with potassium and sodium across the cell membrane. In this way, NKCC1 plays essential roles in physiological processes, including modulating neuronal excitability.
The activity of NKCC1 increases in several pathological conditions; this is why NKCC1 inhibition shows great potential in treating idiopathic and secondary forms of autism (autism spectrum disorder, or ASD), refractory epilepsy, and other neurological conditions.
Lead Program: IAMA-6 for autism, drug-resistant epilepsy, and Dravet Syndrome
IAMA-6 has shown encouraging in vitro and in vivo proof of concept results in idiopathic and secondary forms of autism and drug-resistant epilepsy. The compound is designed to directly target and inhibit NKCC1 and inhibit neuronal hyperexcitability. Pre-clinical studies have demonstrated that IAMA-6 was safe and well tolerated.
We are currently advancing IAMA-6 for multiple autism spectrum disorders, and this therapy also has the potential to be used in other CNS indications, including drug-resistant epilepsy and Dravet Syndrome.
We expect to begin a first-in-human, Phase 1 clinical study evaluating the safety, tolerability, and pharmacokinetic characterization of single and multiple doses of IAMA-6 in late 2023.
IAMA-299 for cognitive impairment
We are also progressing a preclinical program targeting an undisclosed target clinically validated in several different cognitive disorders of high unmet need.
research collaborations
selected publications
"Preclinical Development of the Na-K-2Cl Co-transporter-1 (NKCC1) Inhibitor ARN23746 for the Treatment of Neurodevelopmental Disorders"
ACS Pharmacol Transl Sci. 2023, 6(1):1-11
A. Savardi, M. Borgogno, M. De Vivo, L. Cancedda
"Pharmacological tools to target NKCC1 in brain disorders"
Trends in Pharmacological Sciences (Cell Press) 2021, 42, 12, 1009-1034
C. Portioli, M. J. Ruiz Munevar, M. De Vivo, L. Cancedda
"Cation-coupled chloride cotransporters: chemical insights and disease implications"
Trends in Chemistry (Cell Press), 2021, 3, 10, 832–849
M. Borgogno, A. Savardi, J. Manigrasso, A. Turci, C. Portioli, G. Ottonello, S. M. Bertozzi, A. Armirotti, A. Contestabile, L. Cancedda, M. De Vivo
"Design, synthesis, in vitro and in vivo characterization of selective NKCC1 inhibitors for the treatment of core symptoms in Down syndrome and other brain disorders”
Journal of Medicinal Chemistry 2021, 64, 14, 10203–10229
A. Savardi, M Borgogno, R. Narducci, G. La Sala, J. Ortega, M. Summa, A. Armirotti, R. Bertorelli, A. Contestabile, M. De Vivo, L Cancedda
"Discovery of a small molecule drug candidate for selective NKCC1 inhibition in brain disorders"
Chem (Cell Press) 2020, 6, 1–24
L. Riccardi, V. Genna, M. De Vivo
"Metal-ligand interactions in drug design"
Nature Reviews Chemistry, 2018, 2, 100–112
G. Deidda, M. Parrini, S. Naskar, I. F. Bozarth, A. Contestabile, L. Cancedda
"Reversing excitatory GABAAR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome”
Nature Medicine, 2015, 21, 318–326
