Staglin Music Festival/NARSAD Rising Star Awardee, 2009
Since continuing work with his Rising Star grant in 2009, Dr. Andrew Pieper of the University of Texas Southwestern Medical Center (UTSWMC) in Dallas has made substantial advances, together with Dr. Steven McKnight also at UTSWMC, towards providing a basis for the development of new treatments for the cognitive problems experienced by patients with schizophrenia. Although additional research and testing must be conducted before human trials can be initiated, this compound (called ‘P7C3’) safely and effectively preserves new neurons as they are born and proliferate in the mouse brain. Moreover, P7C3 "potently blocks the accelerated hippocampal neuronal cell death and cognitive decline that is normally seen in aged rats, thus preserving the ability to learn during aging," Dr. Pieper explains.
In previous research Pieper and McKnight discovered that the npas3 gene, which is disrupted in some patients with schizophrenia and learning disability, governs the proliferation of new neurons in the hippocampus. It was subsequently shown by other investigators that hippocampal neurogenesis is aberrantly low in the brains of patients with schizophrenia. Because the hippocampus is essential to learning and memory formation, malfunctions in this region of the brain are believed to play a role in schizophrenia's cognitive symptoms. "Of the various symptom domains in schizophrenia, the cognitive symptoms have the earliest onset and are most chronic and difficult to treat, and thus place patients at highest risk for morbidity and mortality," says Dr. Pieper. "Tragically, there are no treatment options for this symptom domain."
So, Pieper and McKnight set out to find some. They began with the hypothesis that by fixing faulty neuron proliferation, they could preserve hippocampal-dependent cognition. To pursue this question, they blindly screened 1000 compounds from the UTSWMC chemical compound library in living mice with the hope of identifying new molecules that enhanced hippocampal neurogenesis. Testing on living mice was a first for this type of large screen, and although "technically demanding and risky, we believe that our in vivo discovery strategy offers meaningful advantages over more traditional screening approaches," Pieper explains. Unlike test-tube studies which have so far failed to yield molecules that enhance neurogenesis when administered to living mice, this in vivo screen demanded from the outset that any molecules identified display functional effects in living animals.
Their strategy paid off when, last year, they identified "eight structurally unique small molecules that safely and potently elicit the growth and development of new neurons in the hippocampus," Dr. Pieper says. "Each one of these potentially holds promise for development of a new class of therapeutic agents aimed at treating cognitive symptoms in schizophrenia." Now the team is investigating how these molecules work to enhance neurogenesis. Their lead molecule (P7C3) can be taken orally and prevents cell death of neural precursor cells. P7C3 also stabilizes mitochondria in the face of insults that would otherwise trigger cell death, providing a possible clue to P7C3’s mechanism of action. In addition to the above-mentioned benefits of P7C3 in aged rats, oral administration of P7C3 also fixed structural and functional deficits associated with deficient hippocampal neurogenesis in mice lacking the npas3 gene. As Pieper and McKnight continue to generate more effective analogs of P7C3, it will be exciting to watch their progress in the years to come.
If you'd like to meet Dr. Pieper and ask him about his research in person, please come to the Staglin Music Festival for Mental Health on September 11, 2010. He will be there and will be available to answer your questions after the symposium.
Learn how you can support this research
