Conference organized by the CHDI, Cure Huntington’s Disease Initiative
Huntington’s disease is caused by an autosomal dominant mutation on either of an individual’s two copies of a gene called Huntingtin. One of the major difficulties in identifying better targeted and efficacious therapeutic agents to treat this disease is its complexity as highlighted by the broad spectrum of symptoms. In particular, the presence of multiple and often opposite pathological syndromes, e.g., motor disturbances (chorea and hyperactivity in early stage followed by extrapyramidal type of symptoms such as akinesia or dystonia), mental dysfunction (schizophrenic-like symptoms and aggressive behavior versus depression, apathy and social withdrawal), or cognitive aspects, are clearly reflective of the multifactorial nature of HD, despite its monogenic origin. It is therefore unlikely that a single molecule, targeting a single mechanism would provide the most appropriate solution for treating all the symptoms of the disease. To address this, Rhenovia is developing a systems biology approach that integrates the complex signaling cascades that are progressively disrupted during the course of HD. Although many neuronal systems are affected, dysfunction and subsequent neurodegeneration in the basal ganglia and cortex are the most apparent pathologies and significant evidence has accumulated to indicate that glutamate (Glu) and dopamine (DA) neurotransmission are affected in HD. We therefore are developing a computational model of striatal GABAergic medium spiny neurons (MSN) and their regulation by glutamatergic, dopaminergic, and cholinergic inputs. This model provides detailed information regarding the impact of a variety of drugs targeting receptors, transporters, and voltage-dependent ion channels, the dynamics of which are affected by the pathological gain of function of NMDA receptors. Thus, the model can determine changes in glutamatergic synaptic responses resulting from activation or inhibition of dopamine receptors, and conversely, the effects of glutamatergic agonists and antagonists on dopaminergic responses. Likewise, the model allows to incorporate pathological data to create a HD-like MSN environment and can subsequently be used to discover new targets, or new compounds to optimally reverse the pathological condition observed in HD.
Source: Rhenovia Pharma