生物生物学家:博士. 西尔维娅方 & 讨论AAV治疗的意义


通过研究人类基因组, 澳门正规博彩十大排行平台已经设计了治疗方法来解决遗传疾病的根本原因. 这是澳门正规博彩十大排行平台澳门正规博彩十大排行平台进行研究的指导原则, 这一点在澳门正规博彩十大排行平台研究基因疗法的工作中体现得最为明显. 作为澳门正规博彩十大排行平台扩大澳门正规博彩十大排行平台的 专业技术, we’re looking into many aspects of gene therapy to better understand aspects of this groundbreaking treatment approach that remain a challenge for the scientific community. 在澳门正规博彩十大排行平台的 《澳门十大博彩正规游戏平台》的最新出版物. 但首先, 澳门正规博彩十大排行平台很高兴邀请到方西尔维娅和苏米·古普塔, two of our scientists eager to share with us more about what’s at the cutting edge of gene therapy research.

西尔维娅和苏米,非常感谢你们今天参加澳门正规博彩十大排行平台的节目! 你能简单介绍一下你自己并描述一下你在澳门正规博彩十大排行平台的角色吗?

Soumi古普塔: 我已经在澳门正规博彩十大排行平台工作六年多了. 目前, 我领导临床免疫学小组, where our primary responsibility is to characterize immune responses to our potential therapies, 它们对安全性和有效性的影响, and what adjustments can be made to improve the risk/benefit profile of each candidate medicine.

西尔维娅方: 我在澳门正规博彩十大排行平台工作了将近9年. I feel like I’ve had a few lives here: I was brought in to work with the valoctocogene roxaparvovec team, 血友病A基因疗法的研究进展, where I was responsible for developing the assays for preclinical and clinical studies. 现在我在做一个不同的研究 & 发展, 专注于早期的研究, but I continue to work with the gene therapy research team in trying to answer questions related to AAV gene therapy.

你们对澳门正规博彩十大排行平台在AAV基因治疗中所做的工作都有很大的影响. 你能告诉澳门正规博彩十大排行平台更多关于你在这个领域所做的不同研究吗?

SF: 澳门正规博彩十大排行平台 teams currently have about 58 ongoing studies across six areas of AAV gene therapy research where the scientific and patient advocacy communities have a lot of questions. 这些重点领域是资格, 可预测性/可变性, 耐用性, 依赖预防, 安全, 和re-dosing. 再给药是一个新兴的研究领域, 但澳门正规博彩十大排行平台努力保持在所有潜在的相关研究领域的前沿.

SG: 在我的团队里, 澳门正规博彩十大排行平台正在努力 understand what role the immune response to the AAV plays in each of these areas and how can we overcome it. 关于资格, currently enrollment is largely restricted to those patients that don’t have preexisting immunity to the type of AAV (AAV5) that’s used as a vector for the therapeutic gene. So our partners in bioanalytical sciences have worked with a partner to develop a companion diagnostic to help screen patients for that immunity. This is of interest because it could have implications for expression of the desired protein being targeted by the gene therapy.

最终, 澳门正规博彩十大排行平台正在努力 understand the important determinants of preexisting immunity that impact expression to help us identify if there is a subset of patients with pre-existing immunity that can be safely dosed with AAV gene therapy. We are also engaged in non-clinical studies to assess interventions that may allow us to overcome preexisting immunity. 另外, 澳门正规博彩十大排行平台正在努力 understand whether and how the immune response plays a role in variation of protein expression across patients. 变异是由免疫反应引起的吗? 如果是的话,免疫反应具体是什么?

SF: 是的. And what we’re really trying to understand is what factors within individual patients could lead to variability and 耐用性 in expression. 他们的免疫反应是其中的一个组成部分,但还有很多其他的. 这正是我的团队所关注的. Our belief is that once you identify the mechanism, you then can do something about it.

澳门正规博彩十大排行平台刚刚发表在《澳门十大博彩正规游戏平台》上的研究, we wanted to find out how long the AAV-delivered transgene would persist in the liver, as well as assess 安全 and the factors that cause response variability from person to person. We typically rely on clinical data to understand 安全 and efficacy and we’ve been excited to see a lot of data from our trials, but we still had a lot of biological questions about the fate of the gene therapy once it reaches the liver that we could only answer by analyzing liver tissue directly. 肝活检的数据是难以捕获的,由于该程序的侵入性, but thanks to the altruism of our study participants and their eagerness to contribute to the body of knowledge around this therapeutic option, 澳门正规博彩十大排行平台有一个难得而令人兴奋的机会来分析活检样本. 澳门正规博彩十大排行平台的分析显示肝细胞确实含有治疗性DNA, 剂量越高的参与者体内的含量越高, 正如澳门正规博彩十大排行平台所料.

SG: 是的. 和安全部件对话, one dogma that has existed in the field of AAV gene therapy is that a T-cell response against the AAV capsid leads to the ALT and AST elevations that have been observed along with decreases in transgene expression. 澳门正规博彩十大排行平台对此进行了广泛的研究, 包括临床前和临床, 澳门正规博彩十大排行平台发现这与t细胞假说相反, we don’t necessarily see a clear association with a cytotoxic T-cell response and ALT/AST elevations. So, 澳门正规博彩十大排行平台正在努力, 正如西尔维娅所说, 回去问问是什么导致了这些升高, 如果不是t细胞? 这里有一个更大的机械故事,澳门正规博彩十大排行平台正试图理解和解决.


SG: 一般来说, you would start to think strategically about the safest options for modifying the immune response, 它是触发, 或两个. 澳门正规博彩十大排行平台的预防性类固醇研究就是一个例子. 展望未来, what we learn through the study of clinical immunology can help guide therapeutic 发展 in many ways, 继续为澳门正规博彩十大排行平台提供改善临床结果的最佳机会.

是这样吗 澳门正规博彩十大排行平台的技术中心?

SG: 是的! 澳门正规博彩十大排行平台与 技术中心 密切. 一个例子是澳门正规博彩十大排行平台与Flow Core团队的合作, which is helping us use flow cytometry to test the hypothesis that using liver-directed gene therapy could induce immune tolerance to patients who are using factor VIII replacement therapy, 澳门正规博彩十大排行平台正在研究的另一个领域是什么. 澳门正规博彩十大排行平台也在研究各种检测和测量细胞因子的方法, because it’s difficult to come up with an assay that we can use in the clinic that is sensitive enough and specific enough to do so.


SG: 是的,非常. 澳门正规博彩十大排行平台还在摸索表面, 但我认为澳门正规博彩十大排行平台绝对处于基因治疗的前沿. I do not believe that there is any other company that is doing nearly the amount of work that we’re doing in trying to understand the mechanisms, which contribute to the different aspects like 安全 and efficacy and variability 耐用性.

SF: 基因疗法需要解决一些挑战和未知因素, but I think we’ve done and learned a lot in the past 9 years and we are leading the science regarding AAV gene therapy. I believe gene therapy has the potential to transform lives of many people with severe genetic diseases. The key for success in gene therapy is ongoing investment in understanding and improving the technology so that we can better serve our patients.

Thank you both for your groundbreaking contributions to science and for being so generous with your time.