In theory, I wouldn't mind seeing some gender-blind casting in a production of this show some day. A female Hamilton would be interesting; a lot of women could relate to being told to "talk less, smile more" and feeling they "gotta holler just to be heard". However there would also be a risk of over-egging the show with too many Relevant Issues and New Insights.
Although LMM was just referring to future school productions with his comment, if I were to gender-blind cast on Broadway, I think Janelle Monae (who was mentioned in the celebrity replacements thread for Angelica IIRC) would make a great Jefferson.
Another thought for school productions in 20 years' time - it would be fun for a teacher to cameo as King George, for laughs and to emphasise the young, rebellious America vs old Britain theme. Although it would be nice for a high schooler to get to play the role too.