AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa.
AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa.
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DOI：
10.7554/elife.66240
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发表时间：
2021-04-13
期刊：
影响因子：
7.7
通讯作者：
Cepko CL
中科院分区：
文献类型：
--
作者：
Xue Y;Wang SK;Rana P;West ER;Hong CM;Feng H;Wu DM;Cepko CL
视网膜色素变性（RP）是一种遗传性视网膜疾病，影响全球超过2000万人。日光视觉的丧失通常是由于锥状光感受器的功能障碍/丧失而发生的，锥状光感受器是启动我们的颜色和高敏锐度视觉的细胞类型。目前，除了对有限数量的特定疾病基因进行基因治疗外，还没有有效的治疗RP的方法。为了开发一种疾病基因不可知疗法，我们筛选了20个能够延长体内视锥光感受器存活的基因。在这里，我们报告了一种腺相关病毒载体表达Txnip，它抑制视锥细胞的存活，并提高RP小鼠模型的视力。阻断Txnip与硫氧还蛋白结合的Txnip等位基因C247 S提供了甚至更大的益处。此外，Txnip的拯救作用取决于乳酸脱氢酶B（LdhB），并且与更健康的线粒体的存在相关，这表明Txnip通过增强它们的乳酸催化剂来拯救RP锥。视网膜色素变性是一种遗传性眼病，每4,000人中就有一人患病。它是由视网膜感光细胞的遗传缺陷引起的，感光细胞位于眼睛的后部。虽然视力丧失可能发生在出生时，视网膜色素变性通常涉及视力逐渐丧失，有时导致失明。在弱光下负责视觉的视杆细胞首先受到影响。这种疾病会影响锥状光感受器，这种细胞在白天检测光线，提供颜色和敏锐的视觉。已经确定了大约100个与视网膜色素变性相关的突变基因，但只有少数具有这些突变基因之一的家庭接受了针对其突变基因的基因治疗。目前没有治疗方法可以治疗大量患有这种疾病的人。导致视网膜色素变性的突变直接影响检测昏暗光线的视杆细胞，导致夜间视力丧失。还有一个间接的影响，导致锥光感受器停止工作和死亡。解释这种两步疾病过程的一种理论涉及到这样一个事实，即视锥光感受器是非常活跃的细胞，需要高水平的能量、营养和氧气。如果周围的视杆细胞死亡，视锥光感受器可能会被剥夺一些必需的供应，导致视锥细胞死亡和日光视力丧失。为了验证这一理论，薛等人测试了一种新的基因疗法，旨在缓解营养素的潜在短缺。这些实验使用了三种不同的小鼠品系，这些小鼠与患有视网膜色素变性的人类具有相同的基因突变。基因疗法使用一种称为腺相关病毒（AAV）的病毒将20种不同的基因传递到视锥细胞。测试的20个基因中的每一个都在细胞处理营养物质以提供能量的过程中发挥着不同的作用。在给予治疗后，Xue等人监测小鼠的视力是否受到影响，以及视锥细胞如何反应。20个基因中只有一个，Txnip，使用基因疗法传递，具有有益的效果，延长了所有三种小鼠品系的视锥细胞存活。接受Txnip的小鼠也保留了在视觉测试中辨别移动条纹的能力。进一步的研究表明，激活Txnip迫使视锥细胞开始使用一种称为乳酸盐的分子作为能量来源，这种分子可能比它们通常的燃料葡萄糖更容易获得。这些细胞也有更健康的线粒体-细胞内产生和管理能量供应的隔间。这种对燃料使用和线粒体健康的双重影响被认为是延长视锥细胞存活和功能的基础。Xue等人的这些实验已经确定了一种治疗视网膜色素变性的良好基因疗法候选者，而与引起疾病的基因无关。需要进一步的研究来测试基因疗法的安全性，以及它的有益效果是否会转化为视网膜色素变性患者，以及潜在的其他光感受器不健康的疾病。
Retinitis pigmentosa (RP) is an inherited retinal disease affecting >20 million people worldwide. Loss of daylight vision typically occurs due to the dysfunction/loss of cone photoreceptors, the cell type that initiates our color and high-acuity vision. Currently, there is no effective treatment for RP, other than gene therapy for a limited number of specific disease genes. To develop a disease gene-agnostic therapy, we screened 20 genes for their ability to prolong cone photoreceptor survival in vivo. Here, we report an adeno-associated virus vector expressing Txnip, which prolongs the survival of cone photoreceptors and improves visual acuity in RP mouse models. A Txnip allele, C247S, which blocks the association of Txnip with thioredoxin, provides an even greater benefit. Additionally, the rescue effect of Txnip depends on lactate dehydrogenase b (Ldhb) and correlates with the presence of healthier mitochondria, suggesting that Txnip saves RP cones by enhancing their lactate catabolism. Retinitis pigmentosa is an inherited eye disease affecting around one in every 4,000 people. It results from genetic defects in light sensitive cells of the retina, called photoreceptor cells, which line the back of the eye. Though vision loss can occur from birth, retinitis pigmentosa usually involves a gradual loss of vision, sometimes leading to blindness. Rod photoreceptors, which are responsible for vision in low light, are impacted first. The disease then affects cone photoreceptors, the cells that detect light during the day, providing both color and sharp vision. Around 100 mutated genes associated with retinitis pigmentosa have been identified, but only a handful of families with one of these mutant genes have been treated with a gene therapy specific for their mutated gene. There are currently no therapies available to treat the vast number of people with this disease. The mutations that cause retinitis pigmentosa directly affect the rod cells that detect dim light, leading to loss of night vision. There is also an indirect effect that causes cone photoreceptors to stop working and die. One theory to explain this two-step disease process relates to the fact that cone photoreceptors are very active cells, requiring a high level of energy, nutrients and oxygen. If surrounding rod cells die, cone photoreceptors may be deprived of some essential supplies, leading to cone cell death and daylight vision loss. To examine this theory, Xue et al. tested a new gene therapy designed to alleviate the potential shortfall in nutrients. The experiments used three different strains of mice that had the same genetic mutations as humans with retinitis pigmentosa. The gene therapy used a virus, called adeno-associated virus (AAV), to deliver 20 different genes to cone cells. Each of the 20 genes tested plays a different role in cells’ processing of nutrients to provide energy. After administering the treatment, Xue et al. monitored the mice to see whether or not their vision was affected, and how cone cells responded. Only one of the 20 genes, Txnip, delivered using gene therapy, had a beneficial effect, prolonging cone cell survival in all three mouse strains. The mice that received Txnip also retained their ability to discern moving stripes on vision tests. Further investigations demonstrated that activating Txnip forced the cones to start using a molecule called lactate as an energy source, which could be more available to them than glucose, their usual fuel. These cells also had healthier mitochondria – the compartments inside cells that produce and manage energy supplies. This dual effect on fuel use and mitochondrial health is thought to be the basis for the extended cone survival and function. These experiments by Xue et al. have identified a good gene therapy candidate for treating retinitis pigmentosa independently of which genes are causing the disease. Further research will be required to test the safety of the gene therapy, and whether its beneficial effects translate to humans with retinitis pigmentosa, and potentially other diseases with unhealthy photoreceptors.