Potential Gene Therapy for Rett Syndrome in the Works

A gene therapy aimed at slowing disease progression and improving movement, coordination and communication in children with Rett syndrome, is being developed.

Mostly seen in girls, Rett affects brain development, causing impairments such as progressive loss of motor skills and speech.

“It’s often a full-time job as a parent, because these girls need assistance with all their living skills,” Sanchita Bhatnagar, PhD, said in a press release. Bhatnagar is the study’s lead researcher from the University of Virginia (UVA) School of Medicine.  “I don’t know if this therapy is going to fix all of that [impairments]. But it may be able to help them, and any help will be a big step forward.”

Rett is caused most often by mutations in the MECP2 gene, which is located on the X chromosome and gives instructions for making the MeCP2 protein. This protein is crucial in nerve cell function and communication, and regulates other genes’ activities.

Previous research indicated that MeCP2 suppresses the generation of a type of short RNA molecules — microRNAs (miRNAs) — which regulate gene activity. Loss or altered function of MeCP2 in people with Rett result in abnormal amounts of miRNAs, particularly in nerve cells.

Notably, a large amount of miRNAs were observed earlier in the X chromosome of mammals. Also, previous data suggested that dysregulation of certain miRNAs may contribute to Rett syndrome.

The investigational gene therapy uses a modified, harmless adeno-associated virus to deliver so-called miRNA sponges that soak up the miRNAs to ultimately break them down.

“We are not altering the genomic DNA … just using them [the microRNA sponges] as inhibitors that are delivered through [adeno-associated viral] vectors. These vectors do not go and integrate into the genome, so we hope for minimal secondary effects,” the researchers said.

Promising data obtained in early studies with animal models raise expectations of better quality of life for children with Rett.

“We are seeing that lab animals treated with this gene therapy are more mobile. They’re moving faster, they’re smarter,” Bhatnagar said. “If we can help a child to move more independently, or improve their ability to communicate, I think for a parent, that’s a big win.”

The early-stage studies for the project in Bhatnagar’s lab were supported by the Hartwell Foundation and the UVA Brain Center.

Alcyone Therapeutics is supporting the transition into clinical research. If this therapy proves safe and effective in clinical trials, it ultimately could be approved by regulatory authorities as a Rett syndrome treatment.

“We think what Dr. Bhatnagar has come up with is very elegant, and we are excited about its potential to improve the lives of many patients,” said PJ Anand, CEO of Massachusetts-based Alcyone Therapeutics.

This research could lead to a treatment not only for Rett syndrome, but also for other X chromosome-related diseases, such as fragile X syndrome, a condition that affects children’s development, leading to learning and behavior difficulties.

“The exact same gene therapy product can be used to potentially address diseases that are caused by other genes on the X chromosome. Once we have the initial proof of concept in the clinic for the first disease, we can use much of that same information to move toward clinical trials in other X-linked diseases as well, so it will really be an efficient path forward,” Anand added.