Reza Shahbazi, right, and Jennifer Adair inspect a vial of gold nanoparticles (Robert Hood, Fred Hutch News Service)
28 May 2019. Cancer researchers designed a technique using gold nanoscale particles for safer delivery of edited gene therapies to blood-forming stem cells. The process, created by a team from the Fred Hutchinson Cancer Research Center in Seattle, is described in yesterday’s issue of the journal Nature Materials (paid subscription required).
Researchers from the lab of cell biologist Jennifer Adair are seeking to make edited gene therapies for blood-related cancers safer and more reliable. The gene-editing technique Crispr — short for clustered, regularly interspaced short palindromic repeats — makes it possible to edit genomes of organisms by harnessing bacterial defense mechanisms that use RNA to identify and monitor precise locations in DNA.
Delivering edited genes up to now uses electroporation, electrical pulses to break down cell membranes, or engineered viruses to insert the edited genes inside the target cells. Electroporation, however, runs a risk of damaging target cells, while creating engineered viruses for Crispr delivery adds extra time, cost, and more chance for adverse reactions to the process. Gold nanoscale particles offer an alternative to electroporation and engineered viruses, but this delivery method had not yet been tested on blood-forming stem cells for treatments of blood-related diseases.
“Gene therapy has a lot of potential across many diseases, but the process we have right now is just not feasible in every place in the world,” says Adair in a Fred Hutch statement. “We want to end up delivering gene therapy in a syringe. This gold nanoparticle represents the first possibility we have to do that for blood stem cells.”
The chemistry in gold, say the researchers, can be adjusted to make interactions with cell membranes more reliable. The team led by postdoctoral researcher and first author Reza Shahbazi modified the polarity of the nanoparticles for greater stability and easier acceptance by the cells. Once inside the endosome, the cell’s holding area, gold interacts with the cell to release acids that break open the endosome and allow the replacement gene, a DNA template, and RNA guide to reach the cell nucleus, where DNA is stored.
Inside the nucleus, the RNA guides the replacement gene to the appropriate spot in the target DNA, where edits are made with an enzyme called Cpf1. This enzyme is considered simpler and more accurate with fewer off-site edits than Cas9, the enzyme used most often for Crispr gene editing.
The researchers tested their gold nanoparticle Crispr delivery with blood-forming stem cells on 2 target genes. One target is the C-C chemokine receptor type 5, or CCR5 gene, where mutations may prevent HIV infections. Another target is the genes producing gamma hemoglobin proteins, where a natural on/off switch can be reversed to protect against inherited blood disorders.
The tests so far show the technique returns mixed results. Gold nanoparticle Crispr delivery, say the researchers, successfully edits only 10 to 20 percent of the targeted stem cells, a success rate lower than electroporation. However, the cells that are successfully edited survive and perform better than today’s delivery techniques. In tests with lab mice, the gold-edited stem cells perform better than untreated cells, and continued working for 4 months after infusion.
Despite the mixed results, the researchers believe the findings still demonstrate the value of gold nanoparticles for Crispr editing of blood-forming stem cells. Adair and Shahbazi also applied for a patent on the process.
More from Science & Enterprise:
- Start-Up to Use Crispr for Heart Disease, Gains $59M
- Crispr Made More Immune-System Safe
- Crispr Diagnostics Company Launches with $35M Funding
- Trials Underway Testing Crispr for Blood Disorders
- Infographic – What is Crispr?
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