CRISPR’s Unknown Cousin—The Promising Genetic Boost

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The bio-sensation technology CRISPR-Cas certainly has panache, as evidenced by the latest news of engineering a human embryo for the first time to eliminate an inherited mutation. But there’s another type of genetic enhancement, less novel, less headline-catching, that’s inching us closer to a post-Darwinian world of self-augmenting super beings.

The therapy employs a virus whose DNA has been emptied out and refilled with a healthy human gene. This reprogrammed virus is multiplied in the lab and injected into a patient who has a deficiency or defect in that gene. The virus then enters the cells around it, and releases the healthy gene into their nuclei, where unsuspecting RNA from the host cells print the gene into the protein that’s lacking in the patient.

Unlike CRISPR-Cas, which locates and snips mutated or viral genes from DNA, genetic boosting can address age-driven diseases, where genes such as DNA-repair genes don’t need to be replaced, but rather increased in production. Boosting can also address mutations by supplementing them with a donor gene. Finally, hollowed-out viral vectors, as the emptied and refilled viruses are called, can offer a powerful way to host and bring CRISPR-Cas itself into cells and throughout the body. In fact, behind CRISPR’s Silicon Valley glitz, over the last three years genetic boosting has quietly enabled groundbreaking results for several incurable diseases from hemophilia B to sickle cell disease.

In 2014 for example, St. Jude Children’s Research Hospital in Memphis and University College London, reversed hemophilia B in 10 adults. After injecting a vector with the blood clotting FIX gene, hemophilia B symptoms were reduced by 90 percent in all patients over three years, with no toxic side effects and no more need for blood transfusions. Ongoing trials since then have had the same remarkable results.

Last spring, Necker-Enfants Malades Hôpital in Paris, France, reversed sickle cell disease for the first time ever in a human. After injecting a virus vector containing a gene which produces a protein that transports oxygen from the blood to the body, the patient no longer needed blood transfusions. After 18 months, the person still showed no symptoms of sickle cell disease. Bluebird Bio, a gene therapy company based in Cambridge, MA, is now conducting related clinical trials with promising results.

Last month, Bluebird Bio also reversed another disease called thalassemia for the first time in all four of the patients in its clinical trial. Oddly, not one major media source reported it. Like sickle cell, thalassemia comes from a defect in the HBB gene that transports oxygen from the blood to the body. It is a serious scourge, affecting 280 million people worldwide. After receiving an HBB-filled vector, all four patients stopped needing blood transfusions for more than two years. They had 80 percent normal HBB gene production and no side effects, although they still need to have their iron levels adjusted.

Over the last few months, complete, first-ever reversals of previously incurable diseases have also occurred in animal studies, with little to no press coverage. Last spring, the Boston Children’s Hospital and Massachusetts Eye and Ear, reversed Usher syndrome deafness in mice, a disorder that effects millions of children. The National Institute of Health and Medicine in Paris and Sorbonne University Institute of Vision reversed age-driven glaucoma. The Universitat Autònoma de Barcelona in Spain completely reversed Type 2 diabetes in dogs, it would appear. The Molecular Oncology Programme in Madrid, Spain reversed aplastic anemia, an age-related blood disorder. And the School of Medicine at University of Washington reversed a disease known as x-linked myotubular myopathy in dogs, a genetic defect that causes muscle wasting. Human trials are in the pipelines for all of these conditions.

Today, one of the most successful virus vectors being used is an adeno-associated virus (AAV). Unlike other vectors, AAVs don’t disrupt DNA, but tend to float stably near a specific chromosome, number 19. They also have only one DNA strand, so can’t replicate when the cell divides. That means they can be given in a controlled dose as opposed to multiplying throughout the body, which many other vectors can do.

Despite these successes however, many challenges remain. Immune reactions prevent about 40 percent of patients from being candidates. Vectors are also tiny and can only accommodate tiny genes. Many critical genes involved in devastating diseases are not candidates. Finding vectors that can penetrate a large number of cells is also a hurdle.

And vectors have a daunting past. In 2003, a patient died during a clinical trial aiming to treat a mutation that administers prevents the production of urine. That same year, five out of 20 patients in another trial developed leukaemia a couple of years after vector therapy, and at least one patient died.

Since then, however, major milestones have been achieved. They include reducing immune reactions, improving the ability to penetrate the blood-brain barrier, and enabling the vector to target only certain cells.

CRISPR-Cas is astounding in how it takes advantage of a bacteria’s ability to rid itself of viruses and mutations. But virus vectors can also uniquely address age-driven diseases, where a gene may not need replacement but rather an increase in production.

In the end, one is reminded of the old turtle against the dashing hare. Viral vectors have plodded along since the 1960s, tested now in over 117 clinical trials with mixed results, many of them hugely impressive. They might not have the same biotech cachet as CRISPR-Cas, but they’ve been quietly progressing to the point where we’re getting close to being able to realign genetic production, making people genetically supplemented, genetically balanced, genetically younger—and hopefully, much healthier.

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