By David N. Leff

Last Tuesday, June 1, a 50-year-old retiree named Don Miller became the world's first hemophilia patient to receive a gene-therapy treatment for his disease. At 18 months of age, Miller told BioWorld Today, he was diagnosed as suffering from hemophilia A - total deficiency of the gene for the Factor VIII clotting protein that coagulates blood in response to even minor trauma.

At the University of Pittsburgh, an extra-short needle injected intravenously a truncated cDNA Factor VIII gene sequence driven by a modified Moloney-type retroviral vector into a hand vein of this pioneering patient. Chiron Corp., of Emeryville, Calif. had developed that construct in the just-begun Phase I clinical trial of its gene-therapy approach to hemophilia A.

One day later, at the Children's Hospital of Philadelphia, another Phase I trial, this one of gene therapy for hemophilia B - deficiency of Factor IX - treated its first patient, (who had not gone public with his name). Avigen Inc., of Alameda, Calif., tethered its Factor-IX gene, named Coagulin-B, to an adeno-associated viral vector (AAV) for its Phase I gene-therapy human study. That patient received 11 injections into the muscles of one thigh, to ensure adequate Factor IX protein synthesis.

Research hematologist Katherine High, at the University of Pennsylvania-affiliated Children's Hospital, reported her first patient's treatment on June 10 to a corporate symposium on the program of the American Society of Gene Therapy, meeting in Washington. High is a member of the firm's scientific advisory board. (See BioWorld Today, Jan. 5, 1999, p. 1.)

"It's an interesting fact," she told BioWorld Today, "that the same hemophilia doctor, Margaret Ragni, takes care of both of these patients, our hemophilia B case, her type A. Both patients happen to be from the Pittsburgh area, and are being followed at her hematological center there. Ragni is a distinguished clinical investigator in the field of hemophilia."

Factor IX deficiency is also known as Christmas disease. Another expert in this hemophilia variant is Mark Kay at Stanford University, who collaborates with High. He is also taking part in this Phase I safety and dose-escalation trial.

"We plan to enroll nine to 12 patients in the study," High said, "with a built-in delay of several weeks between each individual, to look for any problems. So, I'm expecting the whole thing to take nine months or so."

"In fact," she observed, "the study would probably be most appropriately described as Phase I/II, because we will be following up on this gene-therapy treatment by measuring circulating Factor IX in the patients' blood. Two percent is considered as therapeutic. In dogs, the highest level we got was 1.4 percent, but 1.5 percent would probably work pretty well too in humans."

The gene sequence of human Factor IX, she observed, "is about 80 percent similar to that in dogs. But Avigen engineered in some features to improve expression that were not present in the canine construct."

Chiron's Lewis Williams is senior vice president of research and development, and chief scientific officer. He told BioWorld Today that, in Chiron's hemophilia A Phase I trial, "we'll be monitoring the patients to see if within weeks or months the therapeutic range will go up. We would like to be above five percent, in the 10 to 20-percent range - or higher. Our preclinical hemophiliac dog models suggest we could get safely into a range well above that."

Chiron's clinical trial will involve five centers, he said, with the number of patients determined by the emerging dose escalation data.

Williams noted that 50 male births per million incur hemophilia type A (Factor VIII) deficiency, compared with 10 per million type B, (Factor IX). Both mutant genes reside on male-linked chromosome X.

Preventing Bleeding Response To Needle

The initial Pittsburgh trial's nurse-coordinator, Kristen Jaworski, recalled that administering the truncated cDNA Factor VIII gene to Miller's hand required "an intravenous push of approximately ten minutes' duration each day for three days. We used a so-called butterfly needle, which is small, because hemophilia patients get stuck so much that they like to use very small needles."

Sticking a needle, whatever its size, into the skin or muscle of a hemophilia patient apparently courts a bleeding episode. To circumvent this effect, both the Pittsburgh and Philadelphia subjects received clotting-factor proteins, VIII and IX respectively, which raised their blood levels transiently to 100 percent that of normal, healthy individuals.

"All patients on the study," Jaworski pointed out, "will have severe hemophilia-A, that is, undetectable Factor VIII blood levels. They have both spontaneous and injury-related hemorrhages, which require frequent Factor VIII replacement - usually two to three times a week. I don't think they're anticipating a cure, just some small increases that might prevent the spontaneous bleeding."

Intravenous Vs. Intramuscular Injection Routes Tested

In one sense, these parallel studies will compare the intravenous and intramuscular injections of the gene construct. Chiron's Factor VIII gene, Williams said, is expressed in the liver and spleen, to which the blood-borne construct will presumably navigate. Avigen's High said "the attraction of this Factor IX protocol is that it's something everybody has had - an intramuscular [IM] injection. So, it's minimally invasive and well tolerated - or at least it was in this trial so far. The other thing I think it's important to point out," she went on, "is that many adults with hemophilia have hepatitis. So, the other way to do this is to put the vector into the liver. Whether that will be safe for individuals with hepatitis is not yet known. But most people with hemophilia should be candidates for an IM approach.

"We are encouraged by the successful initiation of the trial of Coagulin-B," High told her audience at the gene-therapy conference. "Gene therapy may offer the potential to treat a variety of disorders not readily treatable by conventional approaches," she added.

On this score, a separate presentation at the conference concerned "treating thalassemia with an erythropoietin gene," High noted.