AAV-delivery of enhanced potassium channel in refractory epilepsy: CTA-enabling preclinical development programme

癫痫影响总人口的1%；美国330万，欧盟450万，英国67万，全球约5000万**。**约80%的癫痫患者生活在低收入或中等收入国家。癫痫患者往往有更多的身体问题，以及更高的心理问题，包括焦虑和抑郁。癫痫患者过早死亡的风险比一般人群高出三倍。大约70%的癫痫患者会有局灶性癫痫，这是一组不同的癫痫，癫痫发作始于特定的大脑区域。尽管使用了最佳的抗癫痫药物，约35%的患者仍会出现癫痫发作。这组局灶性难治性癫痫患者是一种常见的严重神经系统疾病。癫痫的药物治疗经常失败，因为它会影响整个大脑，引起剂量限制的神经系统副作用，偶尔会导致癫痫发作的矛盾恶化。难治性癫痫患者的合并症发生率很高，癫痫猝死（SUDEP）的年风险为0.5%至1%。目前难治性局灶性癫痫的金标准治疗是切除手术，这仅是一小部分患者的选择。它会破坏引起癫痫发作的脑组织，并有永久性神经损伤的风险。只有20%的局灶性难治性癫痫患者被认为适合进行手术评估；其中，只有25%最终接受切除手术。因此，总的来说，估计只有5%的局灶性难治性癫痫患者接受手术切除。许多患者不愿意接受手术，即使风险/收益比被认为是临床可接受的，因为其不可逆的破坏性。迷走神经和深部脑刺激等替代疗法在很大程度上是姑息性的，新的抗癫痫药物的进一步试验使癫痫不再发作的机会不到5%。因此，迫切需要一种新的、有效的治疗方法来保护重要的脑组织。EpilepsyGTx公司正在开发epy201a作为一种新的基因疗法，具有更具体的作用机制，通过降低癫痫引起回路的兴奋性而不沉默神经元，从而降低癫痫发作的严重程度、持续时间和频率。因此，EPY201解决了大量未满足的需求。该项目旨在通过小鼠疗效、耐受性和毒理学研究建立临床前概念证明，并生成cta的临床前数据包。

Epilepsy affects 1% of the general population; 3.3 million patients in the US, 4.5 million in the EU, 670,000 in the UK and about 50 million globally**.** Around 80% of people with epilepsy live in low or middle income countries. People with epilepsy tend to have more physical problems, and higher rates of psychological conditions, including anxiety and depression. Risk of premature death in people with epilepsy is up to three times higher than in the general population.Approximately 70% of people with epilepsy will have focal epilepsy, defined as a diverse group of epilepsies where seizures start in a specific brain area. Around 35% of patients continue to experience seizures despite optimal anti-seizure medication. This group of patients with focal, refractory epilepsy represents a common and severe neurological disorder. Drug treatment of epilepsy frequently fails because it affects the whole brain, inducing dose-limiting neurological side-effects, and occasionally results in a paradoxical worsening of seizures. Individuals with refractory epilepsy have high rates of comorbidity and a 0.5% to 1% annual risk of sudden unexpected death in epilepsy (SUDEP).The current gold standard treatment for refractory focal epilepsy is resective surgery, which is an option for a limited subset of patients only. It involves the destruction of brain tissue from which seizures arise and carries a risk of permanent neurological damage. Only 20% of patients with focal, refractory epilepsy are deemed suitable for assessment for surgery; of these, only 25% eventually undergo resective surgery. Thus, overall, only an estimated 5% of the overall population with focal, refractory epilepsy undergoes surgical resection. Many patients are unwilling to undergo surgery even when the risk/benefit ratio is deemed clinically acceptable because of its irreversible destructive nature. Alternatives such as vagal nerve and deep brain stimulation are largely palliative and the chance of seizure freedom with further trials of new antiseizure medications is less than 5%.There is thus an urgent need for novel, effective treatments that spares vital brain tissue. EpilepsyGTx is developing EPY201as a novel gene therapy that has a more specific mechanism of action by reducing the excitability of seizure-causing circuits without silencing neurons, leading to decreased severity, duration, and frequency of seizures.As a result, EPY201 addresses a substantial unmet need. This project seeks to establish preclinical proof of concept through mouse efficacy, tolerability and toxicology studies, and to generate a CTA-enabling preclinical data package.