Researcher spotlight: Dr Shilpa Kadam, Kennedy Krieger Institute, Johns Hopkins University

SCIENCE

APRIL 18, 2020

This Saturday, we would like to introduce Dr. Shilpa Kadam. She is an Associate Professor of Neurology with joint appointments at The Kennedy Krieger Institute and Johns Hopkins University School of Medicine. The major focus of her research has been to investigate the mechanisms of epileptogenesis in translationally sound models of neurodevelopmental disabilities. During her training as an ICU resident doctor at Pune Institute of Neurology in India, Dr. Kadam has broad clinical exposure to epilepsy management.

She continued her epilepsy research in Dr. Edward Dudek’s laboratory at Colorado while obtaining her PhD. The first granted U.S. patent of Dr. Kadam’s laboratory was on the age- and sex- dependent role of electroneutral chloride co-transporter in refractory neonatal ischemic seizures. Her laboratory was able to discover intervention to reverse the refractory neonatal seizure by studying neonatal seizure in mice models.

Her laboratory investigates various neurodevelopmental disorders — including SynGAP1 — that result in genetic epilepsy. It is their mission to improve lives of children who are affected by these disorders. Dr. Kadam collaborates with Dr. Rick Huganir’s laboratory to further study SynGAP1 related disorders using in vivo animal models. Furthermore, she is helping to establish a new clinic for SynGAP patients at Kennedy Krieger Institute.

Dr. Kadam continues to investigate pathogenesis of SynGAP 1 mutation while helping to identify evidence-based therapies for patients with SynGAP1 diagnosis. Her laboratory was able to identify abnormal underlying brain activity and high incidence of seizure during sleep by examining mouse model and overnight EEG from SynGAP patients. Her laboratory then discovered using a low dose Perampanel (a FDA approved anti-seizure medication, used in low dose may not prevent seizure) can help correct the high frequency abnormal brain activities during sleep in mice model. Her paper, Low-Dose Perampanel Rescues Cortical Gamma Dysregulation Associated With Parvalbumin Interneuron GluA2 Upregulation in Epileptic Syngap1+/− Mice, came out in the past week in Biological Psychiatry.

Summarizing the paper, Dr. Kadam wrote, “Perampanel is already FDA approved for use in children as an anti-seizure agent however the current dosing paradigm is that of slowing ramping up doses over a few weeks starting with the low-dose. As soon as kids are moved to the high dose side-effects are reported by parents and sometimes the drug is abandoned. What our data show is that low-dose by itself may have beneficial effects unrelated to its anti-seizure effects but ability to correct brain activity during sleep. I’m hoping our paper results in more neurologists trying this approach. There is already some anecdotal information from Texas that a SYNGAPian showed great improvements with low-dose PMP when it was started but had aggravation of side effects when the clinician upped the doses as per general protocol. A human trial would be good however very few clinics have a group of syngap patients at the same clinic.”

The biggest obstacle in her research is funding. She is currently pursuing NIH fund for her research in SynGAP1 haploinsufficiency on network dynamic using EEG both in mouse models and patient overnight EEG recordings. She continues to seek overnight EEG recordings from patient communities.

Dr. Kadam is excited to see ASO mediated therapeutics to help rescue SynGAP 1 level in the brain. She is currently seeking funding to use CRISPR/Cas technologies to create mice models for SynGAP patients to study specific phenotypes and to find potential biomarkers.

Members of the Kadam Lab: Divyam Satyarthi, Pavel Kipnis & Brennan Sullivan @Brennan_Sully.