Scientists Advance Gene Therapy to Clinical Trials

Updated January 31, 2020

Gene therapy has made slow and steady progress over the past four decades, but now, as gene therapies make it into clinical trials, progress is speeding up.

Regulatory agencies like the Food and Drug Administration in the United States and the European Medicines Agency in the European Union are approving more gene therapies because of increasingly convincing clinical trial studies that demonstrate that these intricate therapies are both safe and effective ways for treating inherited diseases.

The CRISPR Solution

CRISPR (clustered regularly interspaced short palindromic repeats) is a process of gene editing. 

The treatment was previously called CRISPR-Cas9 because the procedure pairs an RNA strand with Cas9, an enzyme. CRISPR is the name of the genetic code within a DNA strand while Cas9 is the name of the enzyme used to hone in on and cut away specific genes. 

In essence, CRISPR’s bioengineered molecular snip allows a cell to organically replace the mutated gene with a healthy version. 

Conventional Gene Therapy Breakthroughs

While CRISPR has been attracting the attention of science journalists because it’s even more thrilling than science fiction, conventional gene therapy hasn’t been slacking in the past year, either.

In 2019, scientists enjoyed some significant breakthroughs in repairing mutated genes by using hollowed-out viruses to transport healthy genes into cells. 

After altering cells to contain healthy genes, the scientists then released millions of these genetically engineered cells into either the bloodstream or the bone marrow of patients.

The idea behind flooding the body with a high volume of altered cells was a shotgun approach. Since it was impossible to predict where the new wave of cells would land, doctors hoped that enough of them would land in the right places.

In early experiments, this hit-or-miss strategy went awry, leading to dangerous consequences. For instance, it accidentally activated leukemia-causing genes in patients with severe combined immunodeficiency (SCID-x1).

5 Gene Therapy Challenges

Gene therapy is not a new idea. For the past forty years, scientists have been inserting corrected genes into patients with once incurable genetic diseases. What’s different today is that scientists are now much better at doing it with CRISPR and improved conventional gene therapy techniques.

So why did it take scientists so long to be able to design experimental treatments that were safe enough for making clinical trials that would gain Food and Drug Administration and European Medicines Agency approvals? 

The answer to the challenges in gene therapy is complex because it has multiple layers. 

  1. Scientists struggled to find the right viruses to modify to safely deliver healthy genes to target cells. Since nature has only designed toxic viruses, it was difficult to find the rare ones amenable to detoxification and safe enough for patients. 
  2. Scientists struggled to bypass the immune system. Because the human body requires a high homeostatic balance to survive, the immune system has many safeguards in place to attack any foreign DNA. So even after scientists had modified the best viruses and delivered the right genes to the cells, immune rejection would derail gene therapies. 
  3. Scientists struggled to make a cure stick. Even after scientists overcame the two challenges of finding the right viruses to modify and bypassing the immune system’s rejection response, resulting in successful gene therapies, the cures would not last long. This was because dividing cells would slowly stop reproducing the cells that contained the healthy genes. Over time, the efficacy of the treatment would diminish and patients would require more treatments. 
  4. Scientists struggled with the high number of mutated genes. After overcoming the complexity of identifying mutated genes and then replacing them with healthy versions, scientists still had to deal with inherited diseases caused by multiple types of defective genes. It was difficult enough to deliver one healthy type of gene to cells; identifying all the defective types of genes and ferrying healthy replacement genes to cells made it almost impossible. As many as eight defective types of genes could be causing an inherited disease.
  5. Scientists struggled with inserting the healthy gene in the right place in a cell. Not only do scientists have to find the right cells, but they also have to find the right places in the cells to insert the healthy version of the gene. For instance, placing a healthy gene on top of another critically important gene could disrupt the functioning of that gene. Fortunately, this problem appears to be resolved with CRISPR which has the precision technology necessary to locate the right cells and insert the genes into the right place. 

In the past, progress in gene therapy was slow for two primary reasons. First, research is intricate and complex. Second, scientists could not come up with designs for gene therapy considered ethical, safe, and effective for inherited diseases. Now both these constraints appear to be changing with refinements in CRISPR and breakthroughs in conventional gene therapy.