Tetracycline derivative can modulate SMN expression

Survival of motor neuron centromeric (SMN) genes are involved in spinal muscular atrophy when mutated. This disease is an autosomal recessive disorder that progressively determines the loss of spinal alpha motor neurons, causing death during the childhood.

Deletion in SMN1 gene generates a truncated protein without functionality. In a similar situation another protein of the same family SMN2 is produced in larger amount, but this spliced form is unable to overcome the loss of SMN1 and restore its normal activity. SMN2 lacks an exon (7) important for protein function, this is the reason for which SMN2 cannot completely restore SMN1 activity. Researchers observed that tetracycline derivatives could interfere with splicing mechanism and promote the inclusion of exon 7 into SMN2 mRNA. They identified the less toxic ones in order to modulate SMN2 expression without collateral effects. Rather than the toxicity, the second problem that researchers had to solve was the blood brain barrier crossing because tetracycline derivatives cannot cross this barrier. Scientists proposed firstly an injection into brain, then the use of osmotic pump to internalize these useful drug in SMA patients. Giving the lethality of this disease, it’s important that all routes are checked and considered in order to find the right one.