Antisense Technology for Neural Protection and Repair

脊髓损伤（SCI）是一种严重的疾病，目前尚无有效的治疗方法。对社会的代价是巨大的，因为大多数新病例发生在30岁以下的人身上，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SCI的方法势在必行。我们建议使用一个建立在体外试验筛选反义分子的神经保护。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）组织的原代培养物。这些混合的CNS培养物将通过加入细胞因子IL- 1、谷氨酸或通过机械损伤而受到损伤。总之，这些损伤模拟了SCI的重要方面。利用目前的技术，反义序列将被设计和合成，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。将这些反义序列添加到受损的CNS培养物中，并评估神经保护活性。作为该筛选方案的结果，我们期望确定一小部分反义分子，这些分子证明了疗效，并保证在适当的SCI临床前模型中对等同的人类序列进行额外的研究。最终，我们希望确定一种候选分子，Acorda Therapeutics可以将其用于治疗SCI和相关疾病的人体临床试验。拟议的商业应用：仅在美国，用于脊髓损伤和神经退行性疾病患者护理的财务成本估计每年超过900亿美元。由于这一提议而开发和商业化的任何治疗剂将对神经退行性疾病患者的生活产生深远的积极影响。

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.