Health,Stem Cells, and Technology

Friday, April 8, 2016

UCLA Study - Effective Personalized Medicine Based on Phenotyping

Some scientists and physicians have long predicted that personalized medicine, tailoring drug doses and combinations to people’s specific diseases and body chemistry, would be an important part of future health care. A team of UCLA bioengineers, scientists, and physicians has taken a major step toward that reality. 

After organ transplant, patients are on a merry-go-round of medicines and procedures to make sure that the graft is not rejected. Currently, physicians use dosing guidelines for drugs meant to suppress the immune system, but also use educated guesses in choosing dose, to account for variability in patient response to the drugs and drug-drug interactions.

The research team from the UCLA schools of dentistry, engineering and medicine, developed a revolutionary technology platform called phenotypic personalized medicine, or PPM, which can accurately identify a person’s optimal drug and dose combinations throughout an entire course of treatment. Their research appeared online in the April 6 issue of the journal Science Translational Medicine. Unlike other approaches to personalized medicine currently being tested, PPM doesn’t require complex, time–consuming analysis of a patient’s genetic information or of the disease’s cellular makeup. Instead, it produces a personalized drug regimen based on information about a person’s phenotype, biological traits that may include anything from blood pressure to the size of a tumor or the characteristics of a specific organ.

The PPD relies on algebraic equations to relate phenotype (in this case, trough level of an immunosuppressant, tacrolimus) to input (tacrolimus concentration). By mapping patient response over the course of treatment, the equation produces a two-dimensional (2D) parabola that indicates the next dose that the patient should receive. The parabola shifts as drugs are added or taken away, or as the patient undergoes additional clinical procedures, such as hemodialysis, which can interfere with drug distribution within the body. The PPD approach was tested in four patients and compared to the standard of care, physician guidance. The PPD patients were out of trough range less frequently and for shorter periods of time than controls, suggesting that the equation was predicting next doses accurately.

The PPD approach may have broad applicability beyond transplant medicine, because it is independent of disease mechanism or drug of choice and may therefore personalize regimens for many types of patients.

Saturday, April 2, 2016

Complement-Dependent Pathway and Microglia Inappropriately "Eat" Synapses in Alzheimer's Disease Model


More than 99% of clinical trials for Alzheimer’s drugs have failed, suggesting that our current knowledge of the mechanisms underlying Alzheimer's Disease (AD) is incomplete. This week, a group of scientist from MIT, Harvard, Stanford, and UCSF have identified an important new mechanism by which the synapses in the brain are lost in an animal model of AD. Dr. Beth Stevens, Ph.D., and team, found that a developmental process has gone awry, causing some immune cells (microglia) to "eat" (phagocytosize) the connections (synapses) between neurons. In the development of the brain, a protein called C1q sets off a series of chemical reactions that ultimately mark a synapse for destruction by microglia. The microglia are glial cells that have macrophage-like properties and are resident in the CNS. In the AD model, C1q is highly elevated.

Using two AD mouse models, each of which produces excess amounts of the β amyloid protein (a biomarker of AD), and develops memory and learning impairments as they age, she and her team found that both strains had elevated levels of C1q in brain tissue. When they used an antibody to block C1q from eliciting microglial-based destruction, however, synapse loss did not occur. Microglia only destroyed synapses when β amyloid was present, suggesting that the combination of protein and C1q is what destroys synapses, rather than either element alone.

Professor Stevens has helped to start a company to develop a monoclonal antibody to block C1q for the treatment of AD. However, one must be careful about interpreting these results for the sake of therapeutic development. Using animal models for disease, especially models that don't mimic the etiology of the disease, in this case a transgenic mouse, often don't translate well to the clinic. However, the basic science in these studies is excellent, and gives us very important clues about nervous system function, and one of the pathways that may have gone awry in Alzheimer's.