Neurological Correlates

I’m going to guess that 99% of the people out there either failed to show up for or slept through BIO101 where the whole DNA thing was discussed. But — don’t be turned off just because this post is about DNA and RNA and you can never remember what is what.  DNA encodes RNA which then is a template for ribosomes to make proteins. Got it? Good. Because Fragile X premutations have messed up RNAs that block the ribosomes from making protein.  But — there are small molecules that can straighten out the RNA so that the ribosomes can make protein.  (The protein is good, you want the protein).

Fragile X premutations   – even without any Fragile-X-ish phenotype  – may be prone to higher incidence of neuropsychiatric symptoms, such as attention deficit and alcoholism.  (Previous posts here, and here).

Jumbled up RNAs  prevent protein production, and that low level of FMR1 protein may kick off the series of events that leads to the problems.   In a petri dish at least, using chemicals that unjumble the RNA, protein production resumes to healthy levels. 

Noa Ofer, Pnina Weisman-Shomer, Jeny Shklover, and Michael Fry, “The quadruplex r(CGG)_n destabilizing cationic porphyrin TMPyP4 cooperates with hnRNPs to increase the translation efficiency of fragile X premutation mRNA,” Nucleic Acids Res. 2009 May; 37(8): 2712–2722 (via PMC2677883).

“So what?” you may think, “these small molecules never work, and anyway, they are not specific enough, and plus they have 101 delivery problems for them to actually be any kind of therapeutic drugs. And, you’d need to educate an entire sales force, so the NPV is zero, and they should never be developed, and anyway, why not just use antibody or peptibody therapeutics since there are already known regulatory hurdles anyway?” (This is the argument for making a non-decision when you work at a drug company, and you really don’t want to make a decision, because you could be wrong. But if you don’t decide anything, you can’t be wrong and you’ll get your bonus.)

But give these small molecules a chance. Small molecules targeting specific little molecular targets (here RNAs, but also proteins or even DNAs), are really beginning to become a viable business strategy.

Lately I’ve been looking at aptamers , the sort of unemployed brother in laws of small molecules that no company could really make a go of for the past 20-ish or so years (with exception). The small molecues for Fragile X premutatation target “G-quadruplexes” (and,  strictly speaking aren’t aptamers, per se).

These molecules, like siRNAs, need a boat load of formulaton work for drug delivery, because when you put a little piece of DNA into your mouth, or nose, or blood stream, it gets recognized as something to be chewed up by your local enzymes.  (The delivery aspect is where some people are putting down bets).

( As an aside, recent research points to no correlation of Parkinson’s with Fragile X premutation; I haven’t updated research on “non-symptomatic”  Huntington’s although this is also a trinucleotide repeat disorder).