However, despite strong evidence from preclinical and human cohort studies on a therapeutic benefit of eNOS “recoupling” by the administration of BH4 [78] or its precursors (e.g., sepiapterin or folate) [83], this concept was, until now, not translated to clinical therapy, except for the treatment of phenylketonuria [3]. This evidence concerns the gene NOS3 and phenylketonuria.