Innovative Approach to Neurodevelopmental Disorders Gets Major New Backing

Sanchita Bhatnagar is investigating ways to reactivate healthy-but-inactive chromosomes, in an effort to repair brain damage that has been thought to be permanent.

Sanchita Bhatnagar, an assistant professor of biochemistry and molecular genetics at the University of Virginia, has received a $300,000 Hartwell Individual Biomedical Research Award for her work in neurodevelopmental disorders.

Bhatnagar is one of 12 Hartwell recipients from 10 institutions to receive the award, which will provide support for three years at $100,000 per year.

Each year, the Hartwell Foundation invites a limited number of institutions in the United States to hold an internal open competition to nominate candidates from their faculty who are involved in early-stage, innovative and cutting-edge biomedical research. In the 2017 competition, 17 institutions were invited to participate.

Bhatnagar is focusing her research on an array of brain disorders that develop during childhood, particularly in girls.

“Neurodevelopmental disorders are a group of neuropsychiatric conditions caused by alteration of brain function during childhood growth and development, often presenting with impaired motor function and affecting to various extent self-control, emotions, learning ability and memory,” Bhatnagar said.

“With a high prevalence in boys, neurodevelopmental disorders affect almost 4.6 million children in United States. Many affected children have more than one condition, including cerebral palsy, intellectual disability, autism, attention-deficit/hyperactivity disorder, conduct disorder, as well as certain impairments in vision and hearing. The complex interplay of genetics and environment are known to be important factors in clinical presentation. Unfortunately, NDD is a lifelong condition with no available cure; the only therapy is management of symptoms.”

Surprisingly little is known about the neurologic profile in girls, and certain autism syndromes such as fragile-X and Rett occur exclusively in females. In this regard, the majority of neurodevelopmental disorders have multiple genomic alterations, with mutations known to occur among more than 100 protein-coding genes located on the X chromosome. Bhatnagar’s lab is investigating a high-risk, high-reward treatment option for girls that offers the potential to break new ground in the field of neurodevelopmental disorder therapeutics.

In humans, one functional chromosome is inherited from each parent: a pair of X and Y chromosomes determine a male and a pair of X chromosomes determines a female. During early embryonic development in females, one of the two X chromosomes is randomly and permanently inactivated in all cells other than egg cells, which effectively equalizes expression of X-linked gene products between XX females and XY males. Thus in females, even though dysfunctional genes on the active X chromosome are the cause of neurodevelopmental disorders, each defective cell holds a possible key to a cure if the silenced chromosome can be reactivated.

“I propose a novel therapeutic strategy to compensate for X‑linked gene deficiencies in young girls affected with NDD that will boost the expression of healthy genes from their dormant X chromosome and reverse the behavioral deficits,” Bhatnagar said. “My approach is based upon my discoveries about X chromosome inactivation factors that regulate cell signaling and transcription; and how such factors, even in late stages of growth and development, can be controlled to reactivate the X-linked genes without detrimental effects on cell survival or proliferation.”

Bhatnagar is evaluating lead drug compounds for reactivation in a pre-clinical neuron cell model obtained from a female patient with fragile-X syndrome and in a mouse model of Rett syndrome.

“If I am successful in identifying safe and effective drug candidates, it will lay a foundation for subsequent clinical trials and the latent potential to establish a cure,” Bhatnagar said. “Effective and efficient compensation of X-linked gene deficiencies in young girls with NDD would bring emotional relief to affected families that would be immeasurable.”

This emotional release is part of what drives Bhatnagar.

“During my postdoctoral training, I realized the unmet need for innovative therapeutic approaches and significance of clinical collaborations for transformative research that could ultimately result in life-saving medical breakthroughs,” she said. “At a personal level, I had an opportunity to meet several of these families and, being a mother myself, I could feel the pain of having to see your child suffer from a disease that has no cure.”

UVA has been associated with the Hartwell program, which is prestigious and competitive, since 2006. Margaret Shupnik, an associate vice president for life sciences in the Office for the Vice President for Research, said UVA has had several Hartwell winners in the past five years, including faculty in the schools of Medicine, Engineering and Applied Science and Arts & Sciences. She said the recipients benefit in a variety of ways.

“This is a strong network of scholars, a community of researchers, where people share data and procedures, and mentor each other,” Shupnik said.

She said the Hartwell Awards go to the highest-ranked research universities in the country, and the Hartwell Foundation annually assesses which institutions will be invited to participate.  UVA is considered a top-10 center for biomedical research by the foundation. The candidate selection process is operated through the office of Melur Ramasubramanian, UVA’s Vice President of Research.

A native of India, Bhatnagar received her Ph.D. from the University of Notre Dame and conducted post-doctoral training at University of Massachusetts Medical School. She came to the University in 2015.

“One of the reasons for joining UVA was its evolving scientific community, which has great excitement and offers support for young investigators like me,” she said. “Also, both me and my husband, Dr. Jogender Tushir-Singh, joined UVA as assistant professors. Being new PIs with a young family, we were looking for a workplace that offers a good work-life balance. UVA seemed perfect.”

Former Hartwell recipient John Lukens, an assistant professor in the Department of Neuroscience who also is affiliated with the Center for Brain Immunology and Glia, is very impressed with Bhatnagar and her work.

“The project that she proposed is highly innovative and has the potential to provide much-needed therapeutics for a spectrum of neurodevelopmental disorders, including Rett syndrome and fragile-X syndrome,” he said. “Her work also possesses great translational promise, as she has already identified a number of compounds that are effective in X-chromosome reactivation and can now be tested as therapeutics to treat neurodevelopmental disease.”  

While significant early-stage funding benefits the individual researcher, participating Hartwell institutions also receive recognition in the form of a Hartwell Fellowship. For each nominee selected for an Individual Biomedical Research Award, the sponsoring participating institution receives one Hartwell Fellowship that they are asked to designate to a qualified postdoctoral researcher in the early stage of their career. Each fellowship provides support for two years at $50,000 direct cost per year to enable specialized training in biomedical research. Shupnik said the fellow would be selected in late spring.

“The Hartwell Foundation seeks to inspire innovation and achievement by offering individual researchers an opportunity to realize their professional goals. Our approach is to be unique, selective, thorough and accountable. We provide an opportunity for those we support to make a difference and to realize their hopes and dreams,” Fred Dombrose, president of the Hartwell Foundation, said.

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