Koo,

To follow up a bit on Bear’s post: Apabetalone is a drug that works at the epigenetic (control of DNA expression) level, not the genetic (sequence of DNA) level.  When there is a change (mutation) in the DNA sequence at a coding gene, the protein produced is altered and often non- or dys-functional (think of the CFTR protein in people with cystic fibrosis).  When there is a change in the epigenome (protein-DNA complexes in the cell), there is no change in DNA sequence or the protein produced by a gene, just a change in when and/or to what level the gene is 'turned on' and the protein is produced.  What sequencing and analyzing the human genome led researchers to realize is just how few diseases have a simple genetic basis (i.e. are caused by genetic mutations in a single gene as is the case with cystic fibrosis).  Other diseases may be caused by combinations of mutations at different genes (called epistasis) but even in many of these diseases there is a strong environmental effect or ‘trigger’ event.  In such cases, even people who have a genetic predisposition to developing a disease don’t do so unless an environmental factor (infectious agent, stress, dietary component, air or water contaminant, temperature, etc.) are experienced. These diseases depend on a ‘genetic-environmental interaction.’ In these cases, reversing some of the changes in the body caused by the environmental factor may return the body to its prior non-diseased state.

The disease pathways that apabetalone works on tend be the inflammatory diseases brought about in a body experiencing a constant state of inflammation.  The inflammatory response is an important ‘first responder’ defence mechanism against infection and injury in the body but is not intended to be ‘turned on’ in a continuous state. Chronic inflammation becomes damaging to the body that is supposed to be ‘under protection.’  Chromic inflammation is definitely subject to ‘environmental-genetic interactions’ in many individuals.  Ageing (getting old!) is a risk factor for chronic inflammation but so are also all sorts of lifestyle choices (diet, exercise, alcohol consumption), chance events (exposure to infectious agents or antigens) as well as the underlying genetic predisposition.  The large number of ways in which chromic inflammation damages the body means that many different diseases states can be stopped or reversed if the inflammation is stopped.

Is apabetalone a miracle drug that is too good to be true?  Nope, just a start on addressing the vast majority of human disease states that aren’t caused by single genetic mutations or devastatingly virulent pathogens.  Apabetalone apparently addresses only one type of epigenomic change (lysine acetylation) but there are other epigenetic processes that can be dysregulated (DNA and protein methylation and beyond).  Moreover, the selectivity of apabetalone for the BD2 domain of the BET proteins reduces its toxicity relative to pan-BET inhibitors but likely also reduces its efficacy for some disease states.  So, it is the first of what will be many epigenetic drugs. 

Jupe