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

癫痫影响1%的普通人群;美国有330万患者，欧盟有450万，英国有67万，全球约有5000万 *。大约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，以及更高的心理状况，包括焦虑和抑郁。癫痫患者的死亡风险是普通人群的三倍。大约70%的癫痫患者患有局灶性癫痫，定义为癫痫发作开始于特定大脑区域的不同癫痫组。大约35%的患者继续经历癫痫发作，尽管最佳的抗癫痫药物。这组患有局灶性难治性癫痫的患者代表了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，引起剂量限制性神经副作用，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高，每年发生癫痫猝死的风险为0.5%~ 1%。目前难治性局灶性癫痫的金标准治疗是切除手术，但仅限于少数患者。它涉及破坏癫痫发作的脑组织，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手术评估;其中，只有25%最终接受切除手术。因此，总体而言，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/受益比被认为是临床上可接受的，因为其不可逆的破坏性。迷走神经和脑深部电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发作自由的机会小于5%。因此迫切需要新的、有效的治疗方法，以保护重要的脑组织。EpilepsyGTx正在开发EPY 201作为一种新型基因疗法，其具有更特异的作用机制，通过降低引起癫痫的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，EPY 201解决了大量未满足的需求。该项目旨在通过小鼠有效性、耐受性和毒理学研究建立临床前概念验证，并生成CTA支持的临床前数据包。

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.