Emory University School of Medicine
Director - Emory Special Diagnostic Services Clinic
As a resident at Grady Hospital in the mid-1980s in Atlanta, Georgia, we prided ourselves on the care we gave our patients suffering with sickle cell anemia. A clinic dedicated to managing pain crisis gave the patients a sense of home. Dedicated nurses would get to know the patients and expertise was geographically concentrated which lead to improved care. And the potential promise of gene therapy as a cure was gaining traction, giving hope to these people and the healthcare workers who cared for them. The culprit for of all of this human misery, a missense mutation, which substituted valine for glutamic acid on the beta globin chain, would seem a viable and achievable target for gene therapy, which was just gaining traction. Three decades later that undertaking seems to have been a mirage, as that promise has never been fully realized. However, case reports of success exist (1).
At the request of the editor of this newsletter, Domenica Taruscio, I agreed to write a review of some current article with a genetics theme. Noting, in a pile of New England Journals near my desk, an article titled Gene Therapy in Patients with Transfusion-Dependent Beta-Thalassemia, (2) I was transported back to my residency days caring for sickle cell patients and that largely unachieved dream of gene therapy as a cure.
The accompanying editorial by Alessandra Biffi, MD, reports B-Thalassemia to be “one of the most common genetic diseases in the world”(3). Pediatric patients with transfusion dependent B-Thalassemia do well with allogeneic transplantation, with 90+% disease-free survival if hematopoietic cells are harvested from a matched sibling. Adults sufferers of B-thalassemia do not fare so well as children with this approach and gene therapy is now reported to be “on the way to becoming an alternative curative treatment” for the adult population.
The study was done in France and the United States. There were 22 patients in the two studies, followed for 42 months post-transplant. Patients received a lentiviral vector which encoded the adult hemoglobin with a T87Q amino acid substitution. Depending on the phenotype, all patients either were liberated from transfusion or saw a 73% diminution in transfusion burden. Dr. Biffi concluded that “recent progress in gene therapy has been made by targeting discrete groups of patients with certain immunodeficiencies and hemophilia. B-thalassemia is one of the first examples in which gene therapy could be applied to a large population of patient who reside mostly in developing companies”(3).
Also nestled in the pile of journals was an article on Hearing Loss in Adults, with a section on genetics. The pediatric geneticists need not be reminded that hereditary hearing loss afflicts 1 in a 1000 live births. Moreover, there are 500 plus syndromes that are associated with hearing loss. But there are over a 100 genes that cause “mutations that result in hearing loss that is not associated with disorders of other organs or with dysmorphic features”(4). Hearing loss caused by monogenes mostly affect the cochlea or are detrimental to the sensory hair cell function. Issues of susceptibility are complicated by environmental exposure and the ravages of aging.
And what of our unrequited plan for curing sickle cell patients with gene therapy. Again we turn to the NEJM. A case report is offered, with the explanation that “Gene therapy for patients with this disorder is complicated by the complex cellular abnormalities and challenges in achieving effective, persistent inhibition of polymerization of hemoglobin S. We describe our first patient treated with lentiviral vector-mediated addition of an anti-sickling ?-globin gene into autologous hematopoietic stem cells. Adverse events were consistent with busulfan conditioning. Fifteen months after treatment, the level of therapeutic anti-sickling ?-globin remained high (approximately 50% of ?-like-globin chains) without recurrence of sickle crises and with correction of the biologic hallmarks of the disease.”(1) This has the familiar N=1 aroma that geneticists are trying so hard to overcome. But we like to think progress is being made of all these fronts.
(1) Ribeil JA, Hacein-Bey-Abina S, Payen E, Magnani A, Semeraro M, Magrin E, Caccavelli L, Neven B, Bourget P, El Nemer W, Bartolucci P, Weber L, Puy H, Meritet JF, Grevent D, Beuzard Y, Chrétien S, Lefebvre T, Ross RW, Negre O, Veres G, Sandler L, Soni S, de Montalembert M, Blanche S, Leboulch P, Cavazzana M. Gene Therapy in a Patient with Sickle Cell Disease. NEJM. 2017;376 (9):848.
(2) Thompson AA, Walters MC, Kwiatkowski J, et al. Gene Therapy in Patients with Transfusion-Dependent Beta-Thalassemia. NEJM. April 19, 2018; 378(16):1479-1493.
(3) Biffi A. Gene Therapy as a Curative Option for B-Thalassemia. Editorial. NEJM April 19, 2018. 378(16):1551-1552.
(4) Cunningham LL, Tucci DL. Hearing Loss in Adults. NEJM. 21 Dec 2017. 377:2465-2473.Back to News List