CN112469465B - 使用交变电场抑制病毒感染的方法或装置 - Google Patents
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Abstract
可通过在目标区域中施加交变电场达一段持续时间,抑制所述目标区域中的病毒感染。所述交变电场具有一定频率和场强,使得当将所述交变电场施加于所述目标区域中达所述持续时间时,所述交变电场抑制病毒感染所述目标区域中的细胞。任选地,使用交变电场方法抑制病毒感染可与将抗病毒剂递送至所述目标区域组合,使得在施加所述交变电场的同时在所述目标区域中存在治疗有效剂量的所述抗病毒剂。
Description
相关申请的交叉参考
本申请要求于2018年7月10日提交的美国临时申请62/695925的权益,所述临时申请通过参考以其全部结合至本文中。
背景
病毒为细小的胞内专性寄生物。病毒包含核酸,该核酸含有对宿主细胞的合成机器进行编程以进行病毒复制所必需的遗传信息,并且在最简单的病毒中病毒还包含保护性蛋白外壳。
为了感染细胞,病毒必须附着于细胞表面,渗透到细胞中,并变为充分地脱壳,以使其基因组可被病毒或宿主机器接近以进行转录或翻译。病毒的繁殖通常导致细胞损伤或死亡。生产性感染导致子代病毒的形成。
先前已经显示,当细胞在经历有丝分裂的同时暴露于特定频率范围内的交变电场(AEF)时,AEF会破坏有丝分裂过程并引起凋亡。如美国专利7016725和7565205中所述,该现象已成功地用于治疗肿瘤(例如成胶质细胞瘤、间皮瘤等),所述专利各自通过参考以其全部结合至本文中。并且在治疗肿瘤的情况下,这些交变电场称为“TTFields”(或“肿瘤治疗电场”)。TTFields疗法非常适合于治疗肿瘤的原因之一是TTFields在有丝分裂期间选择性地破坏分裂中的细胞,并且显然对未在分裂中的细胞没有影响。而且由于肿瘤细胞比人体内的其他细胞分裂频繁得多,因此将TTFields应用于受试者将选择性地攻击肿瘤细胞而不会伤害其他细胞。如美国专利9750934中所描述的,也已成功地显示同样的现象对破坏细菌是有用的,所述专利通过参考以其全部结合至本文中。并且在此同样,这种方法非常适合于破坏细菌的原因之一是,细菌细胞比人体内的其他细胞分裂快得多。
发明概述
本发明的一个方面涉及抑制病毒感染目标区域中的细胞的第一方法。第一方法包括以下步骤:在目标区域中施加交变电场达一段持续时间,所述交变电场具有一定频率和场强,其中当将所述交变电场在目标区域中施加达所述持续时间时,所述交变电场抑制病毒感染目标区域中的细胞。
在第一方法的某些情况下,目标区域为活受试者内的区域,并且所述交变电场对于受试者为安全的。在这些情况中的某些情况下,目标区域为无肿瘤的。
第一方法的某些情况进一步包括以下步骤:将抗病毒剂递送至目标区域,使得在进行所述施加的同时在目标区域中存在治疗有效剂量的抗病毒剂。
在第一方法的某些情况下,交变电场的频率在50-500 kHz之间。在第一方法的某些情况下,交变电场的频率在25 kHz-1 MHz之间。在第一方法的某些情况下,交变电场的频率为约200 kHz。
在第一方法的某些情况下,交变电场的场强在1-5 V/cm RMS之间。在第一方法的某些情况下,交变电场的场强为约1.2 V/cm RMS。
在第一方法的某些情况下,所述持续时间在1-48小时之间。在第一方法的某些情况下,所述持续时间在2-14天之间。在第一方法的某些情况下,所述持续时间为约48小时。
在第一方法的某些情况下,交变电场的取向在所述持续时间期间于至少两个方向之间反复切换。在这些情况中的某些情况下,交变电场的取向大约每秒切换一次。
在第一方法的某些情况下,交变电场的取向在所述持续时间期间于第一方向和第二方向之间反复切换,并且第一方向大致垂直于第二方向。
在第一方法的某些情况下,交变电场经电容耦合式电极施加于目标区域。
附图简述
图1为用于两个体外实验的平皿的示意图。
图2为在本文所述的各种实施方案中用于将AC电压施加于电极的AC电压发生器的示意图。
图3描绘对于第一实验相对于对照的相对感染效率。
图4描绘对于第二实验相对于对照的相对感染效率。
图5A和5B分别描绘在示例性实施方案中用于将电极定位于受试者的身体上的前视图和后视图。
以下参考附图详细描述各种实施方案,其中相似的指涉数字表示相似的元件。
优选实施方案的详述
出人意料的是,发明人已经表明交变电场也可用于抑制病毒感染。这些结果令人惊讶,因为AEF通过在有丝分裂期间破坏分裂中的细胞而在上述背景下发挥作用。但与肿瘤细胞和细菌不同,病毒不会通过有丝分裂进行复制。
现将描述两个建立AEF可抑制病毒感染的体外实验。这些实验使用Novocure™Inovitro™测试设置来测量从ThermoFisher Scientific获得的人类胚胎肾脏HEK293FT细胞的慢病毒感染。
Inovitro™测试设置包括8个平皿形状的容器,每个容器的形状和尺寸均定制以容纳培养物,并且图1为这些平皿中的代表性一个的示意图。每个平皿30包括一起形成平皿的陶瓷侧壁31和底部面板32。多个电极41-44设置于陶瓷侧壁31的外表面上的选定位置处,使得当将培养物定位于容器中时,在所述多个电极41-44之间施加电压感应出通过培养物的电场。更具体地讲,(a)在电极41和42之间施加AC电压沿第一方向感应出通过培养物的交变电场,和(b)在电极43和44之间施加AC电压沿第二方向感应出通过培养物的交变电场。在图1实施方案中,由于电极41-44置于陶瓷侧壁31上,第二方向垂直于第一方向。注意的是,如果将电极的一个子集(例如电极41和42)移动小角度(例如小于10°),则第二方向会大致垂直于第一方向。
现转向图2,AC电压发生器20产生施加于第一对电极41、42和第二对电极43、44的信号。AC电压发生器20以选定频率在第一对电极41、42之间施加AC电压一秒钟,然后以相同频率在第二对电极43、44之间施加AC电压一秒钟,并在实验的持续时间内重复这两个步骤顺序。该系统还包括热传感器(未显示),并且如果感测到平皿30的温度变得太高,则AC电压发生器20将减小施加于电极的AC电压的幅度。
在第一实验中,将肾细胞暴露于编码绿色荧光蛋白(GFP)的慢病毒。对于该实验,使用带有磷酸钙转染试剂TLP5916和Precision LentiORF RFP Control DNA OHS5832的DharmaconTMTrans-Lentiviral包装试剂盒。感染复数为5,并将场强为1.2 V/cm RMS的200kHz AEF施加于培养物持续48小时。如上所述,AEF的方向每秒切换一次。除了不施加AEF之外,对照经受完全相同的条件。在48小时时段结束时,基于GFP的存在来鉴定受感染的细胞(即GFP的存在意味着细胞受到感染)。通过流式细胞术分析作为表达病毒编码的GFP的细胞%来测量感染效率。在经AEF处理的培养物中受感染细胞的百分比为30%;和对照培养物中受感染细胞的百分比为47%。然后计算相对感染效率(相对于对照)。结果示于图3中,如下所示:对于200 kHz AEF,与对照细胞(100±5.4%, p<0.01, student T检验)相比较的相对感染水平为64±0.5%。
在48小时时段结束时,观察结果表明,在经AEF处理的培养物和对照两者的实验过程期间细胞均在分裂,并且在经AEF处理的培养物和对照之间对细胞总数没有显著影响。对此的一种可能解释可能是相对短(48小时)的处理持续时间加上所用的低场强,因为可在不低于27℃下施加AEF。
除了使用100 kHz AEF代替第一实验中使用的200 kHz AEF之外,第二体外实验在所有方面均与第一实验相同。该第二实验的结果如下:在经AEF处理的培养物中受感染细胞的百分比为51%;和对照培养物中受感染细胞的百分比为64%。然后计算相对感染效率(相对于对照)。结果示于图4中,如下所示:对于100 kHz AEF,与对照细胞(100±3.7%, p<0.01 p<0.0005, student T检验)相比较的相对感染水平为80±2%。
在上述两项体外实验中,AEF的频率为100或200 kHz。但是在备选实施方案中,AEF的频率可为50-500 kHz之间的另一频率。在其他实施方案中,AEF的频率可在25 kHz-1 MHz之间。在其他实施方案中,AEF的频率可在1- 10 MHz之间。在仍然其他实施方案中,AEF的频率可在10-100 MHz之间。对于给定类型的宿主细胞和给定类型的感染或试图感染宿主细胞的病毒的每种组合,可根据预期用途通过实验确定最佳频率。优选地,注意确保选定的频率不会不利地加热目标区域。
在上述两项体外实验中,AEF的场强为1.2 V/cm RMS。但是在备选实施方案中,可使用不同的场强(例如在0.2-1 V/cm RMS之间、在1-5 V/cm RMS之间或在5-25 V/cm RMS之间)。对于给定类型的宿主细胞和给定类型的感染或试图感染宿主细胞的病毒的每种组合,可根据预期用途通过实验确定最佳场强。
在上述两项体外实验中,将AEF施加持续48小时。但是在备选实施方案中,可使用不同的持续时间(例如在1-48小时之间或在2-14天之间)。在一些实施方案中,可周期性地重复施加AEF。例如,可每天施加AEF达两个小时持续时间。
在上述两项体外实验中,AEF的方向在两个垂直方向之间以一秒钟的间隔进行切换。但是在备选实施方案中,可以更快的速率(例如以1-1000 ms之间的间隔)或以更慢的速率(例如以1-100秒之间的间隔)切换AEF的方向。
在上述两项体外实验中,通过将AC电压以交替顺序施加于在2D空间中彼此分开90°设置的两对电极上,在两个垂直方向之间切换AEF的方向。但是在备选实施方案中,可通过重新定位电极对来在不垂直的两个方向之间或者在三个或更多个方向之间(假设提供另外的电极对)切换AEF的方向。例如,可在三个方向之间切换AEF的方向,所述三个方向各自由其自身电极对的放置确定。任选地,可以定位这三对电极,使得所得的场在3D空间中彼此分开90°设置。在其他备选实施方案中,电极不必成对布置。参见例如在美国专利7565205中描述的电极定位,所述专利通过参考结合至本文中。在其他备选实施方案中,场的方向完全不必切换,在这种情况下,可以省略第二对电极43、44 (图1所示)。
在上述两项体外实验中,由于将导电电极41-44设置于陶瓷侧壁31的外表面上,并且侧壁31的陶瓷材料起电介质作用,因此将电场电容性耦合到培养物中。但是在备选实施方案中,可将电场直接施加于培养物而无需电容耦合(例如通过修改图1中所示的配置,使得将导电电极设置于侧壁的内表面而不是侧壁的外表面上)。
在上述两项体外实验中,将人类胚胎肾脏HEK293FT细胞定位于平皿30内的目标区域中(图1中所示),并使用慢病毒感染那些细胞。在目标区域中施加交变电场抑制病毒对目标区域中细胞的感染。在备选实施方案中,可使用不同的细胞类型和/或不同的病毒类型。
通过将AEF施加于活受试者身体的目标区域,可将这些结果应用于体内背景。在目标区域中施加交变电场将抑制病毒对目标区域中细胞的感染。这可例如通过以下方式完成:将电极定位于受试者的皮肤上或皮下,使得在那些电极的选定子集之间施加AC电压会将AEF施加于受试者身体的目标区域。例如,在其中所讨论的病毒一般地在肺中定殖的情况下,电极51-54可如图5A和5B所示定位。在一些实施方案中,电极被电容耦合于受试者的身体(例如通过使用包括导电板并且还具有设置在导电板和受试者的身体之间的介电层的电极)。但是在备选实施方案中,可以省略介电层,在这种情况下,将使得导电板直接与受试者的身体接触。
AC电压发生器20 (图2中所示)于第一对电极51、52之间以选定的频率(例如200kHz)施加AC电压持续第一时间段(例如1秒),这感应出AEF,其中场线的最重大分量平行于受试者身体的横轴。然后,AC电压发生器20于第二对电极53、54之间以相同频率(或不同频率)施加AC电压持续第二时间段(例如1秒),这感应出AEF,其中场线的最重大分量平行于受试者身体的矢状轴。然后在治疗的持续时间内重复这两个步骤顺序。任选地,可在电极处包括热传感器(未显示),并且如果感测到电极处的温度变得太高,则AC电压发生器20可配置为减小施加于电极的AC电压的幅度。在一些实施方案中,可以添加一对或多对另外的电极对并将其包括在该顺序中。例如,当添加图5A和5B中所示的另外电极对55、56,并且AC电压发生器20将AC电压施加于那些电极时,其将感应出AEF,其中场线的最重大分量平行于受试者身体的纵轴。注意到用于该体内实施方案的任何参数(例如频率、场强、持续时间、方向切换速率和电极的放置)可如上文结合体外实施方案所述的那样变化。但是必须注意确保交变电场始终对受试者保持安全。
在体内背景中,AEF可施加于无肿瘤的目标区域(例如第一人的肺)。或者,可将AEF施加于含有肿瘤的目标区域(例如不同人的肺)。
在任何上述实施方案中,AEF的施加可与将抗病毒剂递送至目标区域组合,使得在进行AEF施加的同时在目标区域中存在治疗有效剂量的抗病毒剂。
由于AEF可抑制病毒感染,因此施加AEF可防止新细胞感染所造成的损伤(细胞功能的改变、细胞死亡或转化)、停止病毒繁殖和传播以及避免其对受感染的人的健康造成影响。
基于AEF的抗病毒疗法也可用于保护未受感染的健康个体免受威胁性感染的侵害,如在与受感染个体密切接触的医务人员的情况下(尤其是在病毒性疾病的急性期,此时感染性颗粒可在血液、皮肤损伤、唾液等中发现,并且可通过直接或间接接触(例如经液滴或气溶胶)传播)。
基于AEF的抗病毒保护也可由免疫系统受到抑制的个体(如在先天性免疫缺陷、器官移植、癌症等的情况下)使用,这些个体缺乏机体的天然强力防御能力,因此对机会性感染极为敏感。
另外,抑制病毒感染对于仍在进行的病毒性疾病的进展可能有巨大的重要性。人类免疫缺陷病毒(HIV)为病毒的实例,该病毒在人体中维持在临床上休眠的状态达长时间段,然而在此期间,病毒会持续存在并复制,特别是在淋巴结中。随着时间的推移,感染后易感免疫细胞的数量下降,并发展AIDS (获得性免疫缺陷综合征)。停止病毒感染的连续循环将控制其中的传播并防止疾病的进展。
此外,如果与另外的抗病毒药物组合,基于AEF的抗病毒疗法可潜在地显示甚至更高的效果。
尽管已经参考某些实施方案公开了本发明,但是有可能对所描述的实施方案进行多种修改、改变和变化而不背离如所附权利要求所限定的本发明的界限和范围。因此,旨在本发明不限于所描述的实施方案,而是具有由以下权利要求的语言及其等同物所限定的全部范围。
Claims (12)
1.一种用于抑制病毒感染目标区域中的细胞的装置,其包括:
AC电压发生器(20),其用于在所述目标区域中施加AC电压和交变电场达在1小时-48小时之间或在2天-14天之间的持续时间,其中所述交变电场具有在25kHz-1 MHz之间的频率和在1-5V/cm RMS之间的场强,并且当将所述交变电场施加于所述目标区域中达所述持续时间时,所述交变电场抑制所述病毒感染所述目标区域中的所述细胞。
2.根据权利要求1所述的装置,其中所述目标区域为活受试者内的区域。
3.根据权利要求2所述的装置,其中所述目标区域为无肿瘤的。
4.根据权利要求1-3中任何一项所述的装置,其中所述交变电场的频率在50kHz-500kHz之间。
5.根据权利要求1-3中任何一项所述的装置,其中所述交变电场的频率为200kHz。
6.根据权利要求1-3中任何一项所述的装置,其中所述交变电场的场强为1.2V/cmRMS。
7.根据权利要求1-3中任何一项所述的装置,其中所述持续时间为48小时。
8.根据权利要求1-3中任何一项所述的装置,其中所述交变电场的取向在所述持续时间期间于至少两个方向之间反复切换。
9.根据权利要求8所述的装置,其中所述交变电场的取向每秒切换一次。
10.根据权利要求1-3中任何一项所述的装置,其中所述交变电场的取向在所述持续时间期间于第一方向和第二方向之间反复切换,并且第一方向垂直于第二方向。
11.根据权利要求1-3中任何一项所述的装置,其中所述交变电场经电容耦合式电极(41,43)施加于所述目标区域。
12.根据权利要求1-3中任何一项所述的装置,其中所述装置与用于在施加所述交变电场的同时递送至所述目标区域的治疗有效剂量的抗病毒剂联合使用。
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KR20210030971A (ko) | 2021-03-18 |
WO2020012364A1 (en) | 2020-01-16 |
AU2019301956B2 (en) | 2023-04-13 |
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US12011588B2 (en) | 2024-06-18 |
BR112020025692A2 (pt) | 2021-03-16 |
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JP2023184550A (ja) | 2023-12-28 |
US20230173266A1 (en) | 2023-06-08 |
CN112469465A (zh) | 2021-03-09 |
JP2022511220A (ja) | 2022-01-31 |
CA3103070A1 (en) | 2020-01-16 |
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