Two people were hurt and are in the hospital in serious condition.
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Jeffersonville Police Lt. Isaac Parker says the house exploded just before 5 a.m. Sunday.
The blast not only destroyed the house, but also as many as 15 neighboring houses.
Officials say several pieces of debris pose a safety risk which has led the Jeffersonville Building Commissioner to evacuate and condemn several nearby homes because of damage.
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No word yet on what caused the explosion.
Jeffersonville is along the Ohio River river, just north of Louisville, Kentucky.
There are several pieces of debris in elevated positions that pose a safety risk if they were to fall. Numerous houses near the explosion have been condemned by the Jeffersonville Building Commissioner due to structural damage.