It has been demonstrated in mice that restoring SynGAP production to normal levels, even in adult mice, results in an improvement of the phenotype. Restoration of SynGAP levels directly addresses one of the underlying causes of disease, it doesn’t just treat downstream effects.
Haploinsufficiency means there is one “working” copy of the SYNGAP1 gene which does not produce enough protein for typical function. Making the working copy work harder (or better), is one way of up-regulating (making more) SynGAP. There are several known techniques to up-regulate SynGAP production.
Note for missense variants: many of the techniques described in this section may result in up-regulation of both the working and broken copies of SYNGAP1. In the majority of cases, this does not appear to be a problem as the product of the broken copy is discarded by the body. However, some missense mutations may be dominant negative, meaning they have a detrimental effect on the working copy, or gain-of-function, meaning that they may cause a problem other than not enough SynGAP protein. Up-regulating a dominant negative or gain-of-function variant may cause problems, so every missense variant needs to be analyzed to ensure it is actually a loss-of-function variant that is safe to up-regulate.
已经在小白鼠上证明，即使在成年小鼠中，将 SynGAP 的产生恢复到正常水平，也会导致表型的改善。SynGAP 水平的恢复直接解决了疾病的根本原因之一，而不仅仅是治疗下游效应。
单倍体不足意味着有一个 SYNGAP1 基因的“工作”拷贝不能产生足够的蛋白质来发挥典型功能。让工作副本更努力（或更好）工作，是上调（制造更多）SynGAP 的一种方式。有几种已知的技术可以上调 SynGAP 的产生。
注意错义变体：本节中描述的许多技术可能会导致 SYNGAP1 的工作副本和损坏副本上调。在大多数情况下，这似乎不是问题，因为损坏的副本的产品会被主体丢弃。然而，一些错义突变可能是显性负性的，这意味着它们对工作拷贝或功能获得有不利影响，这意味着它们可能会导致除了 SynGAP 蛋白不足之外的问题。上调显性负性或功能获得变体可能会导致问题，因此需要分析每个错义变体以确保它实际上是可以安全上调的功能丧失变体。
Antisense Oligonucleotides (ASO’s)
ASO's are samll fragments of RNA that can bind to a gene’s mRNA and modify its expression. For SYNGAP1, the end goal is to get the one functional copy of the gene to produce more “working” SynGAP protein. ASOs are precision drugs developed to target specific diseases.
ASO 是DNA的小片段，可以与基因的 mRNA 结合并改变其表达。对于 SYNGAP1，最终目标是获得基因的一个功能拷贝，以产生更多“工作”的 SynGAP 蛋白。ASO 是针对特定疾病开发的精准药物。
ASO’s are already approved by regulators and available on the market for several diseases, most notably Spinal Muscular Atrophy (SMA). ASO’s targeting other haploinsufficiency disoders are already in pre-clinical trials or clinical trials, for example:
ASO 已获得监管机构的批准，并可在市场上用于治疗多种疾病，尤其是脊髓性肌肉萎缩症 (SMA)。ASO 针对其他单倍体不足症的疾病已经在临床前试验或临床试验中，例如：
Praxis Precision Medicines PRAX-222 (pre-clinical) for SCN2A
Stoke Therapeutics' MONARCH study (clinical phase 1/2A) for Dravet Syndrome
GeneTX and Ultragenyx GTX-102 trial (phase 1/2) for Angelman Syndrome
用于 SCN2A 的Praxis Precision Medicines PRAX-222（临床前）
Stoke Therapeutics 的Dravet 综合征 MONARCH 研究（临床 1/2A 期）
Angelman 综合征的GeneTX 和 Ultragenyx GTX-102 试验（1/2 期）
ASO’s have been shown to up-regulate (increase production of) working SynGAP in several cellular studies, including:
在多项细胞研究中，ASO 已被证明可以上调（增加产量）有效的 SynGAP，包括：
Stoke’s TANGO technology has positive results for SynGAP
Stoke 的TANGO 技术对 SynGAP 产生了积极影响
ASO'S are a novel technology but one that is proven to work and is progressing for disorders similar to SYNGAP1. There is hope that an ASO targeting SYNGAP1 is not far off. However, ASO’s have some downsides:
ASO'S 是一门新技术，但已被证明有效，并且正在治疗类似于 SYNGAP1 的疾病。希望针对 SYNGAP1 的 ASO 不远了。但是，ASO 有一些缺点：
Like many drugs that need to enter the brain or the central nervous system, delivery is a challenge. ASO’s are currently delivered intrathecally (spinal tap), though there is on-going research to determine a safer way to deliver the treatment to the brain.
ASO’s degrade inside the body and have to be re-administered regularly to maintain effectiveness. The approved ASO for SMA, for example, requires a maintenance dose every four months
与许多需要进入大脑或中枢神经系统的药物一样，递送也是一项挑战。ASO 目前是鞘内给药（脊髓穿刺），尽管正在进行研究以确定一种更安全的方式将治疗传递到大脑。
ASO 在体内降解，必须定期重新给药以保持有效性。例如，批准用于 SMA 的 ASO 需要每四个月进行一次维持剂量。
