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.
已經(jīng)在小白鼠上證明，即使在成年小鼠中衫樊，將 SynGAP 的產(chǎn)生恢復(fù)到正常水平，也會導(dǎo)致表型的改善十艾。SynGAP 水平的恢復(fù)直接解決了疾病的根本原因之一，而不僅僅是治療下游效應(yīng)唠梨。
單倍體不足意味著有一個 SYNGAP1 基因的“工作”拷貝不能產(chǎn)生足夠的蛋白質(zhì)來發(fā)揮典型功能哎垦。讓工作副本更努力（或更好）工作，是上調(diào)（制造更多）SynGAP 的一種方式苦蒿。有幾種已知的技術(shù)可以上調(diào) SynGAP 的產(chǎn)生。
注意錯義變體：本節(jié)中描述的許多技術(shù)可能會導(dǎo)致 SYNGAP1 的工作副本和損壞副本上調(diào)渗稍。在大多數(shù)情況下佩迟，這似乎不是問題，因?yàn)閾p壞的副本的產(chǎn)品會被主體丟棄竿屹。然而报强，一些錯義突變可能是顯性負(fù)性的，這意味著它們對工作拷貝或功能獲得有不利影響拱燃，這意味著它們可能會導(dǎo)致除了 SynGAP 蛋白不足之外的問題秉溉。上調(diào)顯性負(fù)性或功能獲得變體可能會導(dǎo)致問題，因此需要分析每個錯義變體以確保它實(shí)際上是可以安全上調(diào)的功能喪失變體。
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的小片段坚嗜，可以與基因的 mRNA 結(jié)合并改變其表達(dá)夯膀。對于 SYNGAP1诗充，最終目標(biāo)是獲得基因的一個功能拷貝苍蔬，以產(chǎn)生更多“工作”的 SynGAP 蛋白。ASO 是針對特定疾病開發(fā)的精準(zhǔn)藥物蝴蜓。?
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 已獲得監(jiān)管機(jī)構(gòu)的批準(zhǔn)碟绑，并可在市場上用于治療多種疾病，尤其是脊髓性肌肉萎縮癥 (SMA)茎匠。ASO 針對其他單倍體不足癥的疾病已經(jīng)在臨床前試驗(yàn)或臨床試驗(yàn)中格仲，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（臨床前）
??Stoke Therapeutics 的Dravet 綜合征 MONARCH 研究（臨床 1/2A 期）
? Angelman 綜合征的GeneTX 和 Ultragenyx?GTX-102 試驗(yàn)（1/2 期）
ASO’s have been shown to up-regulate (increase production of) working SynGAP in several cellular studies, including:
在多項(xiàng)細(xì)胞研究中，ASO 已被證明可以上調(diào)（增加產(chǎn)量）有效的 SynGAP诵冒，包括：
Stoke’s?TANGO technology?has positive results for SynGAP
? Stoke 的TANGO 技術(shù)對 SynGAP 產(chǎn)生了積極影響
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 是一門新技術(shù)凯肋，但已被證明有效，并且正在治療類似于 SYNGAP1 的疾病汽馋。希望針對 SYNGAP1 的 ASO 不遠(yuǎn)了侮东。但是，ASO 有一些缺點(diǎn)：
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
與許多需要進(jìn)入大腦或中樞神經(jīng)系統(tǒng)的藥物一樣豹芯，遞送也是一項(xiàng)挑戰(zhàn)悄雅。ASO 目前是鞘內(nèi)給藥（脊髓穿刺），盡管正在進(jìn)行研究以確定一種更安全的方式將治療傳遞到大腦铁蹈。
ASO 在體內(nèi)降解宽闲，必須定期重新給藥以保持有效性。例如握牧，批準(zhǔn)用于 SMA 的 ASO 需要每四個月進(jìn)行一次維持劑量容诬。
