Pasadena Researcher Uncovers Missing Link in Neuropsychiatric Cell Therapy

HuntingtonMedical Research Institutes senior scientist’s work considered a game-changer

We’veall heard the phrase “better together” throughout the pandemic over and overagain; however, that is exactly what Dr. Anju Vasudevan, Huntington MedicalResearch Institutes’ (HMRI) senior research scientist and scientific director forthe angiogenesis and brain development research program, has found to be truein her recently published co-authored study on brain cell therapy forpsychiatric and neurological disorders ranging from autism and schizophrenia toepilepsy and severe depression.

Vasudevan and her colleagues’ work published on July 13 in Molecular Psychiatry is considered to be a game-changing breakthrough uncovering why cell-based therapies are failing, and providing a missing link in the process, that when the right vascular cells are paired with neuronal cells, they work together successfully for brain repair and improvement of disease symptoms.

Researchershave long known that understanding brain cell development is vital tounderstanding and treatment of neuropsychiatric diseases since they hold thekey for regeneration. One population of brain cells referred to as theGABAergic interneurons, have the capacity to produce the neurotransmitter GABA,which serve as a signal to guide the interneurons to the right path and areinvolved in critical functions like memory, language and thoughts. Deficits inGABAergic interneurons in the cerebral cortex have been implicated inneuropsychiatric diseases and are a candidate for cell-based therapy, since itis important to replace what is lost, for successful brain repair.

Inmore recent years, human cell-based therapies are a treatment that have gainedattention, for instance in the case of Parkinson’s disease, as an alternativeto prescription drugs or the “shotgun method,” which only treat some symptoms,and can impact many neurotransmitter systems in the brain. But, to date formany other neurological and psychiatric diseases, cell-based therapies have yetto reach clinical trials due to challenges that need to be overcome.

“Cell-basedtherapy is a transplantation of cells into the brain. For transplantation to beefficient, cells should rapidly travel and integrate with the host braincircuitry in a short time frame. However, on their own, human GABAergicinterneurons take several months to migrate after transplantation inpreclinical models of disease,” explains Vasudevan. “While studying themechanics of the cells, we discovered that these GABAergic neuronal cells mustbe paired with their vascular counterpart, the embryonic forebrain specificendothelial cells for faster, effective therapy.”

“Inshort,” adds Vasudevan, “we were able to replicate the close neurovascularinteractions of the developing forebrain and prove their critical role inguiding the GABAergic interneurons to their final destination in the adultbrain.”

Vasudevansays that there is great diversity in vascular populations in the forebrain,and her lab has previously shown how abnormalities in specific brain bloodvessels can directly contribute to mental illness. The vascular cells alsoproduce GABA and have GABA guiding components that differ from theinterneurons. The team tapped into this knowledge and experience to generatehuman vascular embryonic forebrain like cells and used them in combination withGABAergic interneurons to reduce abnormal behavioral symptoms in a psychiatricdisease model.

“Thinkof this new cell-based therapy as a story of unity through diversity,” explainsVasudevan, “by combining the unique aspects of two different cell types, wewere able to bring out the best in both.”

Thestudy used a GABA pathway component – the GABAA receptor beta 3 subunit(GABRB3) to isolate and generate this new human vascular cell product. This setof the vascular cells is unique to the embryonic forebrain and different fromthe vascular cells produced in other organs of the body; it is one of the manycritical findings from Vasudevan’s work at HMRI that will aide scientists inthe longer journey to use cell-based therapies for brain disorders.

“Onein four people in the world suffers from a neuropsychiatric disorder,” addsVasudevan. “That’s 450 million people. Of those, nearly 1 million peoplecommits suicide annually. Today, as a result of the impact of the pandemic, wefear that number could increase substantially. It truly stresses the importanceof our work, and the continued need to fund and advance the cell-basedtherapies forward.”

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