WASHINGTON DC – In the 2023 Presidential symposium at last week’s American Society of Human Genetics (ASHG) conference, three speakers invited by the Society’s president, Brendan Lee, showcased progress that illustrated, in Lee’s words, “the power of diagnosis and the power of therapy.”

“It is not a Sisyphean task,” Lee said.

Opening proceedings was Dennis Lo, MD, PhD, a pioneer in the field of noninvasive prenatal diagnosis and liquid biopsy.

In 1997, Lo’s team showed that the fetus releases cell-free DNA (cfDNA) that is detectable in maternal blood by 10 weeks gestation. By 2008, his group showed that random sequencing of cfDNA in plasma, followed by mapping those sequences back to their respective chromosomes, could be used to measure chromosome ratios. This allowed the detection of Down syndrome with an accuracy of 99%. Entering clinical practice in 2011, millions of these tests are now performed around the world every year.

Lo and colleagues have also shown that this technology can be used for the early detection of cancer. An excellent example is nasopharayngeal cancer (NPC), which is associated with Epstein-Barr Virus (EBV). Using two rounds of cfDNA screening a month apart, the test reveals individuals at heightened risk of NPC. If both tests are positive, the patient undergoes an endoscopy and additional testing. In a survey of 20,000 subjects in Hong Kong, Lo’s group detected 34 NPC cases, most in stage I. All but one has survived; this early detection has reduced NPC mortality ten-fold. In a second round of screening four years later, 24 additional cases were detected.

Lo has introduced the term “fragmentomics.” It turns out that fetal cfDNA fragments are a bit shorter on average than maternal DNA in the circulation. Now, his group is experimenting with long-read sequencing having relied for more than a decade on short-read sequencing. In pregnancy and cancer, Lo said, 15–30% cfDNA is found in long DNA fragments. “In the last 25 years,” he explained, “we’ve just been looking at text messages from pregnancy. Now we can look at Word documents!”

Therapeutic advances

Lee’s second speaker was Donald Kohn, MD, a leading pediatric hematologist at the University of California, Los Angeles, who has pioneered gene therapies for autoimmune diseases and other blood disorders.

Gene therapy offers three main advantages, Kohn said: 1) a single “one-and-done” treatment; 2) potential treatments for unmet medical needs; and 3) the ability to test efficacy in trials with just a few dozen patients. Over the past few years, gene therapies have been approved for hereditary forms of blindness (Luxturna), spinal muscular atrophy (Zolgensma), hemolglobinopathies (Zynteglo), hemophilia (Hemgenix), and Duchenne muscular dystrophy (Sarepta).

Working with Claire Booth, PhD, University College, London, Kohn’s team has conducted trials for patients with adenosine deaminase deficiency (ADA-SCID)—a form of severe combined immune deficiency—and recently reported exciting progress using base editing for the treatment of other hereditary forms of SCID.

Kohn then reviewed progress in sickle cell disease (SCD), where patients have an average lifespan of 45 years. Multiple approaches are showing promise in the clinic, including gene addition with lentiviral vectors (Bluebird Bio); siRNA disruption of the BCL11A erythroid enhancer; and targeting of gamma-globin promoter sequences to boost gene expression. Base editing is showing promise in directly editing the SCD mutation in the beta-globin gene. And the Vertex exa-cel trial is speeding toward FDA approval next month.

Precision oncology

In the final talk of the session, oncologist Olufunmilayo Olopade, PhD, at the University of Chicago, delivered a rousing presentation on precision medicine for breast cancer. She started by recalling “an amazing Black family” in the early 1990s, in which a 34-year-old woman arrived for breast cancer testing with every member of the family and a five-generation family tree. The proband would die of ovarian cancer, but since the discovery of BRCA1, Olopade has been championing the use of genetic testing in routine cancer care.

Olopade highlighted the racial disparity in breast cancer mortality in the United States. In the 1970s, she said, there were no statistically significant differences because of the absence of effective drugs. But since the availability (to some) of mammography and tamoxifen, she said, Black women have a significantly higher mortality for ER-positive cancer despite a lower incidence. Overall, she said, there is a 40% mortality gap.

She went on to discuss the need for demographically appropriate reference genomes and the need to develop biomarker-informed therapies. The goal is to “target the right drug at the right time,” she said. She is currently working toward a polygenic risk score that will help screen Black breast cancer patients.

The ultimate goal, she said, is mainstream genetic testing. “If genetic testing was available, would you take it?” she asked. The goal is to develop assays that all patients can afford, otherwise, the result will simply be widening healthcare disparities. “Then we’ll get to personalized care,” Olopade said.

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