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Byline: Ron Brauner, Lily Wu, Hillel Laks, Masaki Nonoyama, Frank Scholl, Oleg Shvarts, Arnold Berk, Davis C. Drinkwater, Jing-Liang Wang Abstract: Objective:Allograft-targeted immunosuppressive gene therapy may inhibit recipient immune activation and provide an alternative to systemic immunosuppression. We studied the optimal technique and efficacy of intracoronary gene transfer of viral interleukin-10 and human transforming growth factor-[beta].sub.1 in a rabbit model of heterotopic heart transplantation. Methods: Replication-defective adenoviral vectors were constructed, expressing viral interleukin-10 (AdSvIL10) or transforming growth factor-[beta].sub.1 (AdCMVTGF-[beta].sub.1). Intracoronary delivery of vectors was accomplished ex vivo by either bolus injection or slow infusion. The allografts were implanted heterotopically in recipient rabbits and collected 4 days after the operation. Vector dose was 4 x 10.sup.9 to 6 x 10.sup.10 pfu/gm of donor heart. Transfer was confirmed by DNA amplification for both genes. Gene product expression in tissue was quantified by immunoassay and visualized by immunohistochemical staining. Results: Allograft viral uptake was only 9.9% [+ or -] 2.4% with bolus injection, but increased to 80.5% [+ or -] 6.8% at 1 ml/min infusion rate (p = 5 x 10.sup.-14). Uptake ratio was not affected by vector quantity or slower infusion rates. Transforming growth factor-[beta].sub.1 was consistently detected in allografts infected with AdCMVTGF-[beta].sub.1, but not with control adenovirus or AdSvIL10. Expression was proportional to infused vector quantity and reached 10 ng/gm of allograft at infused 10.sup.10 pfu/gm. Transforming growth factor-[beta].sub.1 was also detected in recipient's serum at less than 1 ng/ml. Viral interleukin-10 was detected in minor amounts only ( Article History: Received 3 July 1996; Revised 19 September 1996; Revised 21 October 1996; Accepted 13 December 1996 Article Note: (footnote) [star] Read at the Twenty-second Annual Meeting of The Western Thoracic Surgical Association, Maui, Hawaii, June 26-29, 1996., [star][star] Address for reprints: Hillel Laks, MD, Division of Cardiothoracic Surgery, UCLA Medical Center, 62-182A Center for the Health Sciences, 10833 Le Conte Ave., Los Angeles, CA 90095., a 12/6/79880

An adenovirus with the herpes simplex virus gene may be used to infect ovarian cancer cells to inhibit or even stop their reproduction. Researchers studied the effect of an adenovirus with the herpes simplex virus thymidine kinase gene followed by ganciclovir treatment on laboratory samples of human ovarian cancer cells and on immunodeficient mice injected with human ovarian cancer cells. Ovarian cancers exposed to the adenovirus were more susceptible to treatment with ganciclovir. Mice treated with adenovirus and ganciclovir had lower tumor burdens and no abdominal tumors.

Inherited dyslipidemias are important risk factors for the premature development of coronary artery disease. One example is an inherited deficiency of low density lipoprotein (LDL) receptors that leads to the syndrome familial hypercholesterolemia (FH). We have used FH as a model for developing new approaches for treating this group of disorders by somatic gene therapy. Experiments in animal models that led to the initiation of a clinical trial of homozygous FH will be presented in this review. Am J Cardiol 1993;72:59D-63D)

The two most common hereditary lung disorders in Caucasians, [[Alpha].sub.1]-antitrypsin ([[Alpha].sub.1]-AT) deficiency and cystic fibrosis, have their major clinical manifestations in the lung. Rapid advances in biotechnology have resulted in a variety of gene therapy strategies for the potential treatment of these disorders. Three vector systems--plasmid, retrovirus, and adenovirus--have been evaluated for their possible utility in transferring genes in a fashion that would either alter the milieu of the lung or directly alter the genetic program of lung parenchymal cells. Two general strategies can be used: ex vivo modification of autologous cells with subsequent transplantation to the patient and in vivo modification with an appropriate vector containing the exogenous gene. Studies carried out in experimental animals show that it is theoretically possible to treat both [[Alpha].sub.1]-AT deficiency and cystic fibrosis with gene therapy if the safety hurdles can be overcome to minimize the risks involved.