scientist clinician and patient seeks that holy grail that will remedy disease. will almost certainly be required to ensure sufficiently broad and early correction of the survival-of-motor-neuron 2 (both copies of in a person must be disrupted for the Pralatrexate disease to occur. However humans have two paralogous SMN genes. The other SMN gene is usually highly similar to with only a handful of sequence differences. One of these lies at nucleotide position 840; the thymidine residue in activates option splicing and excludes exon 7 from the majority of transcripts generated and in Pralatrexate turn results in the generation of a truncated SMN protein that is rapidly degraded (Fig. 1). Physique 1 Option Messenger RNA (mRNA) Splicing as a Target for Small-Molecule Therapies The SMN protein plays an integral role in the spliceosomal assembly and processing of premRNA species in all cells. Studies have also implicated it in the processes of transcription the cellular stress response apoptosis cytoskeletal dynamics and axonal transport. Since all patients Pralatrexate with spinal muscular atrophy have at least one intact copy of a single targeted small molecule that suppresses option splicing of mRNA thus ��rescuing�� the full-length mRNA Prokr1 and increasing SMN protein levels has broad therapeutic potential. Unfortunately the early promise of histone deacetylase inhibitors (e.g. valproic acid) provided by cell cultures derived from patients with spinal muscular atrophy and animal models of spinal muscular atrophy has not been realized.4 Off-target toxic effects present a critical major hurdle for these and many other promising small-molecule therapies. Naryshkin and colleagues used a human embryonic kidney-cell line made up of an minigene (a gene fragment made up of both regulatory and coding regions of that are sufficient to retain select functions of the non-mutated gene) to screen a library of small molecules for chemical classes of compounds that promoted the inclusion of exon 7 into mRNA transcripts. They identified three orally available compounds that they designated SMN-C1 SMN-C2 and SMN-C3. They subsequently found that all three compounds altered splicing and increased SMN protein biosynthesis in fibroblasts from patients with spinal muscular atrophy type 1 type 2 or type 3 and from controls (asymptomatic persons with a single deletion) in a dose-dependent manner. They found a similar effect in cultured motor neuron-like as well as neuronlike and glia-like patient-derived induced pluripotent stem cells. Finally they characterized the selectivity of these compounds using RNA sequence analysis to compare treated cells with control cells. They identified only 6 genes (out of 11 714 in which transcription was up-regulated or down-regulated by more than a factor of 2 suggesting a high level of specificity. Most important they found a substantial benefit of these compounds in two different animal models of spinal muscular atrophy across a variety of outcomes relevant to disease pathogenesis including improved survival improved motor function and preservation of motor-unit circuitry. Time will tell whether the apparent promise of these and related compounds will be realized for patients with spinal muscular atrophy to the same extent as has been shown in cultured cells and animal models. Emerging data suggest that a radically altered transcriptome precedes motor neuron degeneration and loss5: reversing downstream effects in symptomatic patients will undoubtedly present a considerable therapeutic challenge. The animal data described by Naryshkin et al. and by others underscore the need for early even presymptomatic treatment intervention. Nonetheless small-molecule therapies remain potential tools to modify the transcriptome in a discrete and targeted fashion and in so doing ameliorate if not cure some types of disease. Footnotes Disclosure forms provided by the author are available with the full text of this article at.