What exactly is “gene therapy”?

In recognition of Rare Disease Day, I thought I would spend some time discussing one of the promising avenues of treating rare diseases: gene therapy. You can learn more about NINDS efforts to address rare diseases from today’s post from NINDS Director Walter Koroshetz on his blog.

These days, you can hardly pick up a newspaper or listen to a radio without hearing something about gene therapy. Once the realm of science fiction, treatments that modify genetic material or its regulation are becoming a reality even as they are largely still experimental. But what is gene therapy; how do we separate the science from the myth; and what’s the big deal that prevents its being available to everyone who might benefit from it?

The term “gene therapy” refers primarily to three different kinds of treatments: treatment with sequences of genetic material called “antisense oligonucleotides”; insertion of a new gene into cells; and the editing of the genes that are already there. Each of these has their own potential applications and diseases and conditions for which they have been proposed as treatment. Each has different risks and side effects, some of which are yet unknown because they are largely experimental therapies. I will discuss each in turn.

Antisense Therapy

Antisense therapy involves blocking the messages sent by genes to make new proteins. To understand how this process works, we must first discuss how proteins are made from genes. Every gene is made up of two strands of DNA that bind to each other like the teeth of a zipper. Each “tooth” in DNA is made up of one of four building blocks that make up our genetic code. For a protein to be made from a gene, the two DNA strands of the gene are unwound from one another and another kind of complementary chain of building blocks, called RNA, is made. This RNA chain, called messenger RNA, provides a copy of the gene that is used to build the corresponding protein.   

Treatment with antisense oligonucleotides, or antisense therapy for short, takes advantage of this process. Antisense oligonucleotides are short chains of DNA that bind to specific sites in the messenger RNA created from a gene. By attaching to the RNA, the antisense oligonucleotide alters the production of the corresponding protein—in some cases, blocking protein production and in other cases modifying sections of the protein. By doing so, they can block a mutated or damaged gene that would otherwise make a toxic protein, or they can act as a brake on a gene that would otherwise force the cell to make too much of a particular protein.

Antisense therapy can even block a mutated portion of a protein from being made and enable cells to “splice” together to make a protein that functions as well or almost as well as normal. This is the strategy that has been recently used to exciting effect in the deadly genetic disease called spinal muscular atrophy, or SMA. Early results of antisense therapy of SMA have shown normal muscle strength in children, some of whom would otherwise have died of the disease by the age of one year.

Antisense therapy is not a permanent cure. Treatment must be repeated about every three  months for the rest of a patient’s life, and many such treatments for neurological disease must be given directly into the fluid around the brain and spinal cord by inserting a needle into the space around the spinal cord (a procedure called spinal tap or lumbar puncture). Some antisense therapy given into the blood by vein can cause kidney or liver problems; we are just learning how to predict antisense safety and modify the antisense oligonucleotides to make them safer and more effective.

Gene Insertion

Putting a new gene into cells requires creating a normal copy of the gene and then delivering it to the patient in such a way that it will make its way into cells, specifically those in the organ(s) that are affected by the disease. Most studies that have tried to do this have taken advantage of how viruses work to cause infections. Viruses attach to cells and “inject” their genetic material into them so that the cells produce copies that eventually become more viruses. The viruses used in gene therapy do not cause disease but work in the same way. They attach to cells and inject genetic material (that the new genes scientists put into them) but unlike disease-causing viruses, they do not  cause the cells to create new copies. Other delivery systems, such as nanoparticles, are being developed for this purpose as well. This form of gene therapy is being tested in diseases where a defective gene prevents cells from making a functional protein. One example is Duchenne muscular dystrophy, a genetic disease in which children do not make full-sized copies of the protein dystrophin. These children develop a progressive loss of muscle function, including deterioration of the heart muscle, and die as young adults.

If an effective copy of a gene could be inserted and made to function as a normal gene would, this kind of gene therapy could be a lifelong cure. The trick is that there are many complicating factors to consider: getting the virus or nanoparticle to the right place; making sure the amount of protein generated by the new gene is correct; ensuring that the cells don’t reject the new gene; ensuring that the wrong cells don’t receive the new protein, as this could be toxic; and avoiding immune reactions to the virus used as the delivery system. We don’t yet know which viruses are best at getting genes to specific organs or cells, and immune reactions to viruses can mean that, if one experimental gene therapy does not work, the patient may not be able to try another one at a later date.

Gene Editing

The final form of gene therapy is called gene editing. This technique currently uses a method that has been in the news lately called CRISPR-Cas, which is a technique scientists have borrowed from bacteria. It essentially allows one to cut out the mutation-containing parts of a gene and replace them with normal copies. This approach is not ready for use in people (the use of this approach in human twin embryos in China resulted in a worldwide, public outcry). We do not yet know the effectiveness and adverse effects of such therapy in people. Approaches that use gene editing are being studied for mutant protein diseases like sickle cell disease and adrenoleukodystrophy. In these diseases, some of the patient’s bone marrow cells can be treated in a test tube while the patient’s remaining bone marrow is wiped out with chemotherapy and radiation therapy. The treated bone marrow cells are then put back into the patient to repopulate their bone marrow and create blood and tissue cells that make the normal protein. Even these are still experimental approaches, but they have begun to show very encouraging results. Once scientists work out the ways to make gene editing both effective and safe, it could be a lifelong cure for these patients.

So once we work out the methods to make these approaches safe and effective, we’ll be able to treat or cure every patient everywhere with a disease for which we know the gene defect, right? Not quite. Unfortunately, there are a few other practical issues that must be addressed first. Most medications in general are not one-size-fits-all for diseases. Aspirin works for some headaches and not for others. Benedryl (diphenhydramine) takes care of some allergies but not others, and it makes some people sleepy and not others. And these are simple molecules! The variability and complexity are could be even greater for gene therapy.

First, for some diseases that affect a particular protein, each patient and each family has a different mutation. This would require a different antisense oligonucleotide, or a different cargo in a viral package, or a different cut-and-paste editing scheme. This creates a huge production throughput and cost issue. It involves custom-making a drug for disease mutations that may each affect one or two or a dozen patients worldwide.

Second, while we know that some of the side effects of antisense oligonucleotides are related to chemical components outside of the building blocks that bind to a particular piece of RNA, others are related to the building block sequence itself. That means that antisense treatments that bind to one patient’s mutation site may have completely different side effects and toxicity than those that bind to another patient’s mutation site. Regulations and requirements for safety may have to include some that are different for each specific oligonucleotide drug. How, then, can the scientists know what they need to do to bring such drugs expediently to the clinic for patients for whom time is of the essence? How do we enhance efficiency of the process of bringing treatments and cures to people without sacrificing safety?

The NINDS is now working with its fellow NIH Institutes and Centers and consulting with its colleagues in industry and the nonprofit sector to create a consortium of sites and experts around the U.S. who will find solutions to these problems of scale and enable, to the extent possible, definition, standardization, and sharing of data and practices so we can make personalized medicine through gene therapies a practical, available, safe, and effective reality.