Human In Vitro Models For X Chromosome Reactivation

Joost Gribnau, PhD

$401,000 AWARDED

The concept of X-reactivation to express the healthy but silent copy of MECP2 has long been identified as a desirable therapeutic strategy for the treatment of Rett Syndrome since it uses the cells natural regulation of MECP2 gene expression. X-reactivation of MECP2 avoids the potential issue of over-expression that could arise with “conventional” gene replacement strategies.

Dr. Gribnau, an accomplished researcher from The Netherlands, has been a key contributor to RSRT’s MECP2 reactivation efforts for several years. With RSRT funding Dr. Gribnau was able to create a highly complex and extremely valuable Rett mouse model used by various labs to screen for compounds that reactivate the targeted mouse Mecp2 gene.

However, mouse RTT is not a perfect model of human Rett Syndrome and human cells have about 5 times more genes that naturally escape inactivation on the X chromosome than mice. Dr. Gribnau will now generate the same successful screening system using human cells to create a human system to validate the results achieved from extensive studies in mice.

He will also explore if down-regulation of Xist (a gene involved in X chromosome inactivation) facilitates activation of MECP2. If successful, these experiments will serve as important confirmation of other important ongoing RSRT-funded projects focused on MECP2 reactivation.

Current Projects