Therapeutic targets
     
Congenia is principally focused on developing inhibitors of the mitochondrial Permeability Transition Pore (mPTP). Mitochondrial permeability transition is an increase in the permeability of the mitochondrial membranes to molecules of less than 1500 Daltons in molecular weight and results as a consequence of the opening of the mitochondrial permeability transition pores.

Mitochondrial Permeability Transition is a phenomenon characterized by the sudden loss of inner mitochondrial membrane potential due to the permeabilization of mitochondrial membranes. The consequences of this phenomenon are:
  • cessation of respiration
  • influx of solutes into the matrix
  • mitochondrial swelling and rupture
  • release of stored calcium
  • release of apoptotic factors
Ultimately, a prolonged opening of the mPTP leads to cell death via apoptosis or necrosis.

Although the exact molecular structure of the mPTP has not yet been elucidated, it has been suggested that several proteins come together to form a macromolecular complex which includes the adenine nucleotide translocase (ANT), the phosphate carrier protein (PiC) and the proyl isomerase, cyclophilin-D (Halestrap 2009, BBA, 1787, 1402-15).

Genetic studies have clearly shown a role for Cyclophilin D in regulating the mPTP and Cyclosporin A, a known cyclophilin inhibitor, has been shown to attenuate mPTP opening (Basso et al 2005, J. Biol. Chem., 280 (19), 18558-61). Mice lacking the gene for cyclophilin-D develop normally, but their cells do not undergo a Cyclosporin A-sensitive permeability transition and they are resistant to necrotic death from ischemia, overload of Ca2+ or free radicals. (Baines 2005, Nature, 434 (7033), 658-62).

Various factors enhance the likelihood of mPTP opening including high mitochondrial Ca2+ levels, accumulation of Reactive Oxygen Species (ROS), depleted adenine nucleotides and high mitochondrial phosphate content. Oxidative damage and calcium dysregulation are a common features of many "age-related" diseases and therefore opening of the mPTP in response to these phenomena has been suggested to be involved in the pathogenesis of several diseases.

Various factors, including calcium overload and oxidative stress, open, in the inner mitochondrial membrane, the mitochondrial permeability transition pore (mPTP). This uncouples oxidative phosphorylation and compromises intracellulare ATP levels eventually leading to necrotic cell death.

Selected readings

Disease Selected Reading
Myocardial Infarction
Effect of cyclosporine on reperfusion injury in acute myocardial infarction. Piot et al. N Engl J Med. 2008 Jul 31;359(5):473-81.
Inhibition of mitochondrial permeability transition pore opening: translation to patients.Gomez et al. Cardiovasc Res. 2009 Jul 15;83(2):226-33
Mitochondrial permeability transition pore as a target for cardioprotection in the human heart. Shanmuganathan et al. Am J Physiol Heart Circ Physiol. 2005 Jul;289(1):H237-42.
Heart Failure
The role of the mitochondrial permeability transition pore in heart disease. Halestrap et al. 2009. Biochim Biophys Acta. 2009 Jan 8
Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure. Nakayama et al. J Clin Invest. 2007 Sep;117(9):2431-44
Cardioncology
In vivo prevention of adriamycin cardiotoxicity by cyclosporin A or FK506. Al-Nasser. Toxicology. 1998 Nov 16;131(2-3):175-81.
Stroke
Protective effects of NIM811 in transient focal cerebral ischemia suggest involvement of the mitochondrial permeability transition. Korde et al. J Neurotrauma. 2007 May;24(5):895-908.
The mitochondrial permeability transition as a target for neuroprotection. Kristal et al. J Bioenerg Biomembr. 2004 Aug;36(4):309-12.
Traumatic Brain Injury
The role of mitochondrial transition pore, and its modulation, in traumatic brain injury and delayed neurodegeneration after TBI. Mazzeoet al. Exp Neurol. 2009 Aug;218(2):363-70
Attenuation of acute mitochondrial dysfunction after traumatic brain injury in mice by NIM811, a non-immunosuppressive cyclosporin A analog. Mbye et al. Exp Neurol. 2008 Jan;209(1):243-53
Alzheimer's disease
Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Du et al. Nat Med. 2008 Oct;14(10):1097-105
The mitochondrial permeability transition in neurologic disease. Norenberg et al. Neurochem Int. 2007 Jun;50(7-8):983-97
Amyotrophic Lateral Sclerosis
The mitochondrial permeability transition pore in motor neurons: Involvement in the pathobiology of ALS mice. Martin et al. Exp Neurol. 2009 Aug;218(2):333-46.
Intrathecal cyclosporin prolongs survival of late-stage ALS mice. Keep et al. Brain Res. 2001 Mar 16;894(2):327-31.
Muscular Dystrophies
Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy. Millay et al. Nat Med. 2008 Apr;14(4):442-7.
Investigation of Debio 025, a cyclophilin inhibitor, in the dystrophic mdx mouse, a model for Duchenne muscular dystrophy. Reutenauer et al. Br J Pharmacol. 2008 Oct;155(4):574-84
The cyclophilin inhibitor Debio 025 normalizes mitochondrial function, muscle apoptosis and ultrastructural defects in Col6a1(-/-) myopathic mice. Tiepolo et al. Br J Pharmacol. 2009 Jul;157(6):1045-52
Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice. Palma et al. Hum Mol Genet. 2009 Jun 1;18(11):2024-31