Dr Robert Hopkin on Emerging Therapeutic, Technological Advancements in Fabry Disease

Robert J. Hopkin, MD, clinical geneticist, Cincinnati Children's Hospital Medical Center, discusses current and emerging therapeutic and technological advancements in the management of Fabry disease.

There are a myriad of exciting new technologies being developed in the treatment of Fabry disease, which may also have therapeutic implications for other genetic conditions, said Robert J. Hopkin, MD, clinical geneticist, Cincinnati Children's Hospital Medical Center.


What are some recent therapeutic or technological advancements in Fabry disease?

Enzyme therapy was first approved in 2001 in Europe and in 2003 in the United States. So, that's been the mainstay. And then the chaperone therapy came along more recently. There are also currently companies that are doing modified enzymes. So, the enzyme as it is coded for in our genes normally doesn't get shared very efficiently and has a fairly short half-life in the bloodstream, and is easily inactivated, as it is transported in the circulatory system.

The current treatments use that unmodified enzyme. So, there are a couple of different groups that are working on modifications to the enzyme. One of them is a pegylated enzyme that reduces recognition of the protein as being abnormal and therefore reduces the risk for antibody formation and infusion reactions. That also increases the half-life in the bloodstream.

There are several groups doing gene therapies. So, 2 different approaches to gene therapy. One is using AAV [adeno-associated virus] vectors to target uptake into the tissues, primarily targeting the liver and making it into a factory for the enzyme. And then the enzyme gets into the circulatory system and is transported to the other cells in the body.

The other gene therapy approach is to harvest stem cells from the circulatory system, use a lentiviral vector to place a copy of the gene into the cells, and then once you've identified the cells that have active expression of alpha-galactosidase, you culture those and then infuse them as sort of an auto transplant into the body.

There's some significant differences between those 2 approaches. The lentiviral one takes longer to get up to maximized enzyme production. It integrates the gene into the DNA in our chromosomes, so each time the cells divide, a new functional copy of the gene is made so that you get increasing enzyme production with timeat least for the first couple of years.

In addition, those cells, being stem cells, kind of get distributed throughout the body. And then some of them will differentiate into specific specialized cells, including glial cells, which means you get some enzyme production in this central nervous system, which, in theory, could be quite beneficial.

The AAV base can be targeted so that you get optimized uptake in the heart, optimized uptake in the liver, optimized uptake in the kidneys, etc. And there are people working on each of those methods and each of those targets for gene therapy.

There's also some work being done to, instead of making enzymes which break down complex lipid molecules, there are a couple of companies working on substrate inhibition therapies. Instead of trying to clear the complex molecules, they just try to inhibit formation of the complex molecules. You can't store what you don't have around, and if that allows for secondary pathways to be able to eliminate the lipid molecules that need to be cleared, they could be very helpful in treatment as well.

Finally, there's some combinations of modified enzyme in gene therapy, where there's at least one group that's making a gene therapy that's a fusion protein, with the active site for the alpha- glucosidase, an enzyme combined with a protein that has more stability in the pH of the blood so that the enzyme that's made gets more effectively delivered to all of the cell types and a higher percentage of it is available for use within the body.

So, lots of exciting new technologies, but those are going to take a little bit longer to get around to current therapies. I think those are sort of the main new technological advancements. And some of those concepts are exciting for Fabry disease, but also have lots of implications for potential treatments for other genetic conditions. So, I think it's an exciting time to be in the field of rare genetic diseases.