Chromium Mesoporphyrin in the Prevention of Neonatal Jaundice

描述(申请人提供)：新生儿黄疸发生在所有新生儿中的60%-70%。它不仅是由胆红素的过度生产引起的，也是由于这种代谢物的一过性排泄失败引起的。溶血性疾病会加重高胆红素血症，如恒河猴同种免疫和ABO血型不合，导致胆红素产量增加，以及导致胆红素排泄减少的疾病。产生胆红素的限速酶是血红素加氧酶(HO)，因此是一个关键的治疗靶点。抑制HO活性已被证明可以保护新生儿免受过量高胆红素血症的影响。血红素类似物，金属卟啉(MPS)，是HO酶活性的强有力的竞争性抑制剂。MPS作为口服治疗药物可能是预防和治疗高胆红素血症的有效方法。在这项提案中，我们将扩展我们对铬中卟啉(CRMP)的初步研究，它是一种有效的HO抑制剂，可在新生小鼠中被口服和光惰性吸收。在预期有阳性结果的情况下，我们建议将这些研究进一步扩展到非人类灵长类新生儿模型。在我们的实验室中，我们继续开发和验证监测体内血红素降解和HO-1转录模式以及体外HO酶活性的方法，以便我们可以评估这两个水平的调控和表达。将这些方法应用于新生小鼠模型是我们对新生大鼠、小鼠和猴子模型工作的自然延伸。该项目的结果将通过提供与CRMP对酶靶标的直接影响、其表达以及随后对新生动物的短期和长期影响有关的空间和时间信息，来帮助设计CRMP的未来临床研究。本申请的具体目的是评估CRMP通过抑制HO活性治疗新生儿黄疸的有效性和安全性，并作为对其在人类新生儿中使用的潜在有效性和安全性的“临床前”IND评估的基础，特别强调对携带血红素的新生小鼠的短期和长期影响。使用新生小鼠模型应该允许在给药CRMP之前进行良好控制的系统研究，CRMP是一种非常有希望的抑制剂，用于治疗新生儿黄疸。 公共卫生相关性：血红素加氧酶(HO)是预防新生儿黄疸的关键治疗靶点。我们一直在研究金属卟啉(MPS)在新生儿黄疸治疗中的有效性和安全性。在这项建议中，我们建议扩大我们对CRMP在小鼠身上的研究，因为CRMP是一种有效的HO抑制剂，可被口服吸收和光惰性。本申请的具体目的是作为对CRMP用于人类新生儿的潜在疗效和安全性的“临床前”IND评估的基础，特别强调对携带血红素的新生小鼠的短期和长期影响。

DESCRIPTION (provided by applicant): Neonatal jaundice occurs in 60-70% of all newborn infants. It is caused not only by an overproduction of bilirubin, but also by a transient failure to excrete this metabolite. Hyperbilirubinemia is exacerbated by hemolytic diseases, such as Rhesus isoimmunization and ABO incompatibility, which result in increased bilirubin production, as well as diseases that result in decreased bilirubin excretion. The rate-limiting enzyme in the production of bilirubin is heme oxygenase (HO), and as such is a key therapeutic target. Inhibition of HO activity has been shown to protect newborns from excessive hyperbilirubinemia. Heme analogs, metalloporphyrins (Mps), are potent competitive inhibitors of HO enzyme activity. The use of Mps as oral therapeutic agents may be an effective approach for the prevention and treatment of hyperbilirubinemia. In this proposal, we will extend our preliminary studies of chromium mesoporphyrin (CrMP), which is a potent HO inhibitor, absorbable orally and photo-inert, in the newborn mouse. In anticipation of positive findings, we propose to extend these studies further to the non-human primate newborn model. In our laboratory, we have continued to develop and validate assays to monitor in vivo heme degradation and HO-1 transcriptional patterns and in vitro enzymatic activity of HO so that we can evaluate regulation and expression at these two levels. Application of these approaches to the neonatal mouse model is a natural extension of our work with the newborn rat, mouse, and monkey models. The results of this project will assist in the design of future clinical studies of CrMP by providing both spatial and temporal information pertaining to its direct effects on the enzymatic target, its expression, and subsequent short- and long-term effects on the newborn animal. The specific aims of this application are directed at evaluating the efficacy and safety of CrMP for the treatment of neonatal jaundice through inhibition of HO activity and serves as a basis for a "pre-clinical" IND evaluation of its potential efficacy and safety for use in the human neonate, with particular emphasis on short- and long-term effects in the heme-loaded newborn mouse. Use of a newborn mouse model should permit well-controlled systematic studies preceding the administration of CrMP, a very promising inhibitor, for the treatment of neonatal jaundice. PUBLIC HEALTH RELEVANCE: Heme oxygenase (HO) is a key therapeutic target in the prevention of neonatal jaundice. We have been investigating the efficacy and safety of metalloporphyrins (Mps) for their potential use in the treatment of neonatal jaundice. In this proposal, we propose to extend our studies of CrMP in the mouse because CrMP is a potent HO inhibitor, absorbable orally and photo-inert. The specific aims of this application serve as a basis for a "pre-clinical" IND evaluation of potential efficacy and safety of CrMP for use in the human neonate, with particular emphasis on short- and long-term effects in the heme-loaded newborn mouse.