If the game were made from scratch from the ground up now, I think the first thing to do would be to recreate all NPC enemies so that they can use the scaling to level technology that zombie apocalypse and rikti invasion enemies do. If the canon stories only use Hellions up to level 10 or 12 or whatever, that's fine... but if there's ever a need for some level 40 or 50 Hellions, just drop them in and let them scale up.
In addition to that, recreate all NPC costuming elements so that they are individual pieces rather than whole body skins like older NPCs are... and then make all of those assets available to players, with maybe the exception of a handful of unique faces for AVs and Signature Heroes (and even for those, create similar variants for player use).
Next up is rework the AE mission designer so that maps are more customizable, allowing mission designers to change colors of walls, floors, and details as well as drop in objects as set decoration just like in the base builder... also allow the mission designer to place spawn points for specific mission content, such as ambushes, traps, environmental damage effects, lighting, etc. And while we're in AE, allow ALL NPC assets to be available including Reichsman, monsters (like tentacles), and giant monsters (outdoor maps only).
And since it's a from-the-ground-up rebuild, I'd say get rid of Origin in character creation process (it's functionally pointless anymore, but too tangled in the code at present to remove) and also rework how powers function so that you can select a power and then customize it's color, animation, and effect appearance. So let's say you want an Ice Blaster that shoots his cold beams from a gun and the effect looks like fire... but functionally, it's still an ice blast power.