Find and Replace: DNA Editing Tool Shows Gene Therapy Promise

Neutrophil being edited with CRISPR/Cas9

Caption: This image represents an infection-fighting cell called a neutrophil. In this artist’s rendering,  the cell’s DNA is being “edited” to help restore its ability to fight bacterial invaders.
Credit: NIAID, NIH

For gene therapy research, the perennial challenge has been devising a reliable way to insert safely a working copy of a gene into relevant cells that can take over for a faulty one. But with the recent discovery of powerful gene editing tools, the landscape of opportunity is starting to change. Instead of threading the needle through the cell membrane with a bulky gene, researchers are starting to design ways to apply these tools in the nucleus—to edit out the disease-causing error in a gene and allow it to work correctly.

While the research is just getting under way, progress is already being made for a rare inherited immunodeficiency called chronic granulomatous disease (CGD). As published recently in Science Translational Medicine, a team of NIH researchers has shown with the help of the latest CRISPR/Cas9 gene-editing tools, they can correct a mutation in human blood-forming adult stem cells that triggers a common form of CGD. What’s more, they can do it without introducing any new and potentially disease-causing errors to the surrounding DNA sequence [1].

When those edited human cells were transplanted into mice, the cells correctly took up residence in the bone marrow and began producing fully functional white blood cells. The corrected cells persisted in the animal’s bone marrow and bloodstream for up to five months, providing proof of principle that this lifelong genetic condition and others like it could one day be cured without the risks and limitations of our current treatments.

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Shattering News: How Chromothripsis Cured a Rare Disease

Karyotype

Caption: Karyotype of a woman spontaneously cured of WHIM syndrome. These chromosome pairings, which are from her white blood cells, show a normal chromosome 2 on the left, and a truncated chromosome 2 on the right.
Source: National Institute of Allergy and Infectious Diseases , NIH

The world of biomedical research is filled with surprises. Here’s a remarkable one published recently in the journal Cell [1]. A child born in the 1950s with a rare genetic immunodeficiency syndrome amazingly cured herself years later when part of one of her chromosomes spontaneously shattered into 18 pieces during replication of a blood stem cell. The damaged chromosome randomly reassembled, sort of like piecing together a broken vase, but it was still missing a shard of 164 genes—including the very gene that caused her condition.

Researchers say the chromosomal shattering probably took place in a cell in the bone marrow. The stem cell, now without the disease-causing gene, repopulated her immune system with healthy bone marrow-derived immune cells, resulting in cure of the syndrome.

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