Antisense Technology for Neural Protection and Repair

脊髓损伤(SCI)是一种破坏性的疾病，没有有效的治疗方法。这给社会带来了巨大的代价，因为大多数新病例发生在30岁以下的人中，而这些人的预期寿命接近正常。因此，开发一种新的、有效的治疗脊髓损伤的方法势在必行。我们建议使用建立的体外实验来筛选神经保护的反义分子。将建立由神经元、星形胶质细胞和小胶质细胞组成的大鼠中枢神经(CNS)组织的原代培养。这些混合的中枢神经系统培养物将受到细胞因子IL-1、谷氨酸或机械损伤的伤害。综上所述，这些损伤模仿了脊髓损伤的重要方面。利用目前的技术，将设计和合成反义序列，以抑制各种蛋白质的产生，这些蛋白质已被证明参与神经损伤后的组织损伤。这些反义序列将被添加到受损的中枢神经系统培养物中，并将评估神经保护活性。作为这一筛选方案的结果，我们希望确定一小部分反义分子，这些反义分子证明了有效性，并证明了在适当的SCI临床前模型中对等同的人类序列进行额外研究的必要性。最终，我们希望确定一种候选分子，Acorda Treeutics可以将其用于治疗脊髓损伤和相关疾病的人类临床试验。拟议的商业应用：仅在美国，治疗脊髓损伤和神经退行性疾病患者的财务成本估计每年就超过900亿美元。由于这一提议而开发和商业化的任何治疗剂都将对神经退行性疾病患者的生活产生深远的、积极的影响。

Spinal Cord Injury (SCI) is a devastating condition for which there is no effective treatment. The cost to society is enormous because most new cases occur in people under the age of 30 and these individuals have a near normal life expectancy. Therefore, the development of a new, effective therapy to treat SCI is imperative. We propose to use an established in vitro assay to screen antisense molecules for neural protection. Primary cultures of rat central nervous (CNS) tissue consisting of neurons, astrocytes, and microglial cells will be established. These mixed CNS cultures will be injured by addition of the cytokine IL- 1, glutamate or by mechanical injury. Taken together, these injuries mimic important aspects of SCI. Using current technology, antisense sequences will be designed and synthesized to inhibit the production of various proteins that have been shown to be involved in tissue damage following neural injury. These antisense sequences will be added to injured CNS cultures and neuroprotective activity will be assessed. As a result of this screening protocol, we expect to identify a small list of antisense molecules that demonstrate efficacy and warrant additional studies of equivalent human sequences in the appropriate pre-clinical models of SCI. Ultimately, we expect to identify a candidate molecule, which Acorda Therapeutics can take to human clinical trials for the treatment of SCI and related conditions. PROPOSED COMMERCIAL APPLICATIONS: The financial cost for the care of patients with spinal cord injury and neurodegenerative diseases in the US alone has been estimated to be in excess of $90 billion annually. Any therapeutic agent developed and commercialized as a result of this proposal will have a profound, positive impact on the lives of patients with neurodegenerative disease.