Housecalls Hero

Genetic Therapies Advancing
March  2018

​In this first Housecalls issue of 2018 we examine a case of chronic granulomatous disease (CGD), one disease of the larger category of immune deficiency disorders. These disorders are often associated with genetic abnormalities that may become prime candidates for genetic therapy. Also in this issue, Dr. Rosace presents a case of Henoch-Schőnlein Purpura. And Dr. Rooney follows up with an ECG Puzzler.

On December 19, 2017, the US Food and Drug Administration approved Luxturna (voretigene neparvovec-rzyl) for the treatment of biallelic RPE65 mutation associated retinal dystrophy. Known as Leber’s congenital amaurosis 2, this disorder causes a lack of production of an enzyme that is essential for converting light to electrical signals in the retina. Patients experience a loss of vision in childhood or adolescence that progresses to complete blindness.

An estimated 1,000-3,000 patients are affected in the US. Treatment is delivered via subretinal injection. The viral vector is a modified adeno-associated virus. This was the first FDA approval for a gene therapy that was not for the treatment of cancer.

The FDA plans to issue a suite of guidance documents in 2018 “for the evaluation and review of gene therapy for different high-priority diseases where the platform is being targeted.” This particular example of gene therapy is in vivo (in living tissue), while the currently approved cancer gene therapies involve extracting human cells, modifying them in the laboratory, increasing the numbers and reintroducing them to the patient.

This in vitro model may become the most effective, because of the benefits of reducing immune response to vectors, targeting specific cell types and increasing the number of “repaired” cells prior to the reinfusion for maximal benefit.

The field of gene therapy has progressed greatly since five of 20 patients treated for Severe Combined Immunodeficiency (SCID) developed acute lymphocytic leukemia or another T-cell lymphoproliferative disorder because of vector activation of proto-oncogenes. Research into vector composition and function has greatly reduced the risk of therapy, and there are at least a dozen US clinical trials ongoing using lentiviral vectors to alter hematopoietic stem cells (HSC).

The diseases being studied include not only CGD but also Beta-Thalassemia, Sickle Cell disease and SCID among others. In addition, there was a recent encouraging report of treatment of Hemophilia B with an adeno-associated viral vector combined with a factor IX
transgene. The treatment halted bleeding episodes in nine of 10 patients treated.

One possible impediment to gene therapy is the cost. It was reported that the cost of Luxturna is $850,000 USD for a one-time treatment. But costs may be a bargain when compared to the lifelong treatment for such diseases as hemophilia or cystic fibrosis.
Research is proceeding cautiously and a lot more needs to be done, but today gene therapy is an exciting area of research that has the potential to cure some debilitating chronic conditions.

George LA, et al. “Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant”, N Engl J Md (2017);377:2215-2227.

Kohn DB, “Historical Perspective on the Current Renaissance for Hematopoietic Stem Cell Gene Therapy”, Hematol Oncol Clin N Am (2017);31:721–735.

Up To Date, last accessed March 2018.