Ask the Expert with Dr. Premi Haynes

Ask the Expert with Dr. Premi Haynes, University of Washington Institute for Stem Cell and Regenerative Medicine

Dr. Haynes is a postdoctoral research fellow in Dr. Daniel Miller’s lab at the University of Washington where she studies the molecular mechanisms of Facioscapulohumeral Muscular Dystrophy. Her grant, entitled “Utilization of Cell-Free DNA (cfDNA) as A Sensitive Biomarker for Clinical Trial End Point for Individuals with FSHD” was recently funded by Friends of FSH Research and we interviewed her to learn more.

Why did you decide to study FSHD during your postdoctoral fellowship?

Translational research has always motivated me as a scientist. I want to understand how disease disrupts biological processes and with this information create therapies which will eventually make a difference in people’s lives. In graduate school I helped establish a skeletal and cardiac biobank with tissue donated from individuals who underwent heart transplant surgery. I studied the proteins that are involved in contraction, the main function of a muscle. I identified some proteins to be dysfunctional but I wanted to dig deeper to understand if their dysfunction started at the level of the DNA. This is when I first read about FSHD. I was intrigued by the genetic and epigenetic complexities of FSHD. I decided to pursue my postdoctoral training in FSHD research to investigate how changes in FSHD DNA lead to skeletal muscle damage.

What is cell-free DNA?

Each cell in your body contains DNA that is ~3.3 billion base pairs in length. Cell-free DNA are chopped up pieces of DNA <170 base pairs in length. They are not enclosed in a cell anymore and are freely circulating in the blood. They can come from damaged and normal cells. The amount of cell-free DNA can change depending on your physiologic state. For example, if you do strenuous exercise you may have a higher amount of cell-free DNA in your blood as compared to when you are at rest. The levels of cell-free DNA can increase after a heart attack or in certain types of cancers.

How is cell-free DNA currently used as a diagnostic tool (outside of the FSHD field)?

Cell-free DNA also called “liquid biopsy” is currently being utilized as a non-invasive prenatal screen. Cell-free DNA of a fetus can be detected in the circulating blood of the mother as early as 7 weeks of gestation. Sex determination and chromosomal abnormalities can be identified early on without the need for invasive procedures.

Similarly, cell-free DNA is being tested in individuals with cancer where studies show correlation between increased levels of cell-free DNA with progression of disease severity.

What sort of information might your work teach us about FSHD biology?

The profile of cell-free DNA is unknown in FSHD. Our study is the first to extract cell-free DNA from individuals with FSHD and compare it to individuals without FSHD. We are utilizing advanced sequencing technologies to ascertain the DNA fragment sizes and track the tissue of origin of cell-free DNA. For example, in healthy individuals most of the cell-free DNA comes from blood cells called lymphocytes. In individuals with breast cancer a portion of the cell-free DNA is derived from the breast tissue. Similarly, due to skeletal muscle damage in FSHD we hypothesize that a portion of cell-free DNA is derived from skeletal muscle. It may also be possible to predict the severity of FSHD either by the concentration and/or profile of cell-free DNA.

How could cell-free DNA analysis benefit FSHD therapeutics development?

Assessing the effectiveness of a therapy in a FSHD clinical trial is a challenge because the disease affects different muscle groups, is highly variable and has a slow progression. A blood biomarker in conjunction with strength testing will be a useful outcome measure for clinical trials. Using cell free DNA as a blood biomarker could reflect the disease pathology objectively and we may be able to quantitatively assess the disease severity. As all muscle groups are exposed to the same circulating blood, cell-free DNA should reflect average disease burden throughout the body. The clearance rate of cell free DNA is ~15 min to several hours which means the acute effects of a drug can be assessed quickly within days instead of months.

Watch our site for updates on Dr. Haynes’ work, which we hope may lead to a sensitive and non-invasive FSHD clinical trial measure.