John D. Fryer, Ph.D.

Dr. John D. Fryer is a professor and inaugural director of the Center for Accelerated Nanotherapeutics. He is a translational neuroscientist who pursues NIH-funded, mechanistic science as well as omics-based discovery analyses to identify new targets and pathways. The overarching goals of his lab are to determine molecular pathways that impinge upon normal central nervous system function and that ultimately result in lasting cognitive and behavioral impairments as occurs in Alzheimer’s disease and related dementias. Most of these projects lie at the intersection of genetics, aging, and neuroinflammation. Below are snapshots of projects currently being studied in his lab.

Nanobody and picobody development. Recently, his lab has launched a small biologics program to develop high-affinity, single-chain camelid antibodies (“nanobodies”), as well as bovine knob-domain only antibodies (“picobodies”), to therapeutically target proteins that are critical in disease pathogenesis. These are currently at various stages of development and will be pursued for T cell based “CAR T” therapies as well as bi-, tri-, and multi-valent therapeutics. This biologics development platform is amenable to a wide variety of diseases and conditions.

Alzheimer’s disease and related dementias. His lab is actively exploring the inflammatory aspects that play a critical role in the etiology of neurodegeneration. Many of these alterations are mediated by microglia (the innate immune cells of the brain), and his lab pioneered studies using alternative, non-activating approaches to profile these cells across neurodegenerative and acute inflammatory states (published in J Ex Med with a searchable database www.fryerlab.com/ribotag). They have also found that Lewy body dementia, a disease that has overlapping but distinct neuropathology, also results in abundant neuroinflammation (published in Brain and searchable via https://fryerlab.shinyapps.io/LBD_CWOW/). Other datasets are being built from a new dual transcriptomic-proteomic AAV-based profiling tool that his lab developed and will also be shared with the scientific community. They employ widely available omics technologies such as single-cell or single-nucleus RNAseq as well as spatial transcriptomics and proteomics. They have developed nanobodies targeting primary pathologies in Alzheimer’s disease (amyloid, tau) as well as major genetic risk factors (APOE, CLU, TREM2) that are being tested for in vivo efficacy in animal models.

Sepsis and acute inflammation. Sepsis is a deadly, acute inflammatory state that can severely impact brain function in survivors, especially in aged individuals, but the genetic and genomic underpinnings that mediate brain damage and dysfunction are unknown. Many pathways and cell types likely play common roles in both sepsis and Alzheimer’s disease. His lab utilizes rodent models as well as pig models of sepsis, along with multi-omic approaches to uncover novel targets and generate new hypotheses to test with rigorous in vivo studies. They are currently developing nano- and picobodies targeting pro-inflammatory cytokines that are critical in mediating the septic response.

Psilocybin and mood disorders. Interest in using psychedelics for a wide variety of disorders has exploded in recent years. For psilocybin, in particular, the interest has led to over 200 registered clinical trials on clinicaltrials.gov for conditions ranging from post-traumatic stress disorder (PTSD), depression and other mood/anxiety disorders, neurodegenerative diseases (Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis), drug abuse disorders, anorexia nervosa, obsessive compulsive disorder (OCD), headache disorders, and autism spectrum disorders. Additionally, as psilocybin is available as “magic mushrooms” for those who seek access via the illicit drug market, many individuals engage in recreational use as well as self-therapeutic use. Both the clinical trial uses and the illicit personal uses involve both low and high doses (i.e. micro- and macro-dosing). Lifetime risk for mood disorders places these conditions among the top public health problems. His lab is studying how the brain responds to both low “microdoses” vs high “macrodoses” to better understand how it achieves clinical benefit.

Brain tumor interface with immune system and neurons. It has been known for quite some time that brain tumors are able to evade the immune system, partly because the brain is an “immune privileged” organ that does not have the same direct access to the full repertoire of immune cells as other organs in the body. While brain tumors are often described as “immunologically cold”, the growing edge of the brain tumor interacts with, and is heavily influenced by, neighboring astrocytes and microglia, the primary immune cells of the brain. In fact, his lab is studying why brain tumors are less common in individuals with Alzheimer’s disease, with the hypothesis that the inflammatory milieu of the Alzheimer’s brain is less permissive to brain tumor establishment/growth. One emerging area of research has been the interaction of brain tumor cells with brain cells that can drive tumor growth depending on specific molecular cues. His lab has generated new tools to discover some of the key molecular mediators produced by brain tumors cells as well as neurons that interface with them and will develop nano/picobodies to therapeutically target them.