An infant born prematurely and dead may well be thevictim of an inherited blood disorder, lethal alpha-thalassemia. All four of its adult alpha-globin genes aremissing or inert, and the unborn fetus cannot survive thein utero switch over from embryonic hemoglobin to nofunctional alpha-hemoglobin at all.

In the medical dictionaries, this genetic death sentencegoes by the name of Hb Bart's hydrops fetalis. (Bart wasthe name of the first patient to be described with this grimcondition.)

Emergency blood transfusions have rescued a handful ofsuch preemie babies born alive, but as moleculargeneticist Chris P szty told BioWorld Today, "It isdifficult to justify prenatal intervention for the prospect oflife-long transfusion dependency."

P szty is a post-doc in the Rubin laboratory at the HumanGenome Center of the University of California LawrenceBerkeley Laboratory. He is first author of a paper titled"Lethal a-thalassemia created by gene targeting in miceand its genetic rescue," in the September issue of NatureGenetics.

He and his co-authors constructed this strain of knockoutmice by gene targeting in embryonic stem cells tospecifically delete both pairs of adult murine alpha-globingenes. Fetuses that inherited the deletion from bothparents died between the 14th and 16th day of a 20-daygestation. This corresponds to human alpha-thalassemiafetuses, which are stillborn in the third trimester of anine-month pregnancy.

A Human Gene To The Rescue

"By breeding human alpha-globin transgenes into thesemice," P szty said, "our group rescued them fromperinatal death."

Deletions in the alpha-globin gene cluster are the mostcommon of all mutations in humans, but most are of littleor no medical consequence. They differ from the beta-thalassemias in more ways than one.

The beta-thalassemias occur mainly in areas bordering theMediterranean Sea, where they produce severe, long-drawn-out disease states. In fact, the very wordthalassemia comes from two Greek words, for "sea" and"blood." Beta-gene deletions are designated MED (forMediterranean).

The alpha syndrome is widest spread in the Philippinesand Thailand, where its gene deletion, labeled SEA (forSouth-East Asia), affects between 4 and 10 percent of thepopulation.

Thalassemia prompted the very first transfer of humangenes with therapeutic intent, which took place just 15years ago this summer. In June and July 1980,hematologist Martin Cline, University of California atLos Angeles, infused globin genes into the veins of twoyoung women suffering from beta-thalassemia, one inIsrael, the other in Italy. His attempt was inconclusive,and earned Cline severe criticism (plus research-grantdeletions) for jumping the gene-therapy gun.

"This mouse model," P szty observed, "should acceleratethe development of gene therapy and hematopoietic stem-cell therapy for treating or curing this human condition."

Next Up: Sickle Cell Anemia

Another, wider-spread, condition for which P szty andthe Rubin lab are now tooling up their approach is sickle-cell anemia.

"To make a model of sickle-cell disease," P szty said,"what people tried in the past was to put human sicklegenes into mice. They didn't get sickling, because the redcell contained not only the human globins but the mouseproteins. These got in the way of the sickling, as opposedto a human patient, who has only the human globins.

"So there's been a pretty long-standing goal to get rid ofthe mouse gene," P szty continued. "One part of ourmodel will be deletion of the alpha-globin gene. Acollaborating lab at the University of Alabama hasdeleted the murine beta-globin gene. So we will breedthese knockout mice together, and then breed in a humansickling transgene.

"That's probably a more important use of this deletionthan lethal alpha-thalassemia," P szty concluded. "In fact,that's the reason I made this mouse.

"We're actually pretty close to having a sickle cellmodel," he said. "I'm hoping a lot of people will want touse it. Depending on how good it turns out to be,certainly it'll be a very useful reagent for gene therapyand drug therapy." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.