Gene Therapy Holds Promise (Again) for an Inherited Immunodeficiency Disease

Gene Therapy Holds Promise (Again) for an Inherited Immunodeficiency Disease

by David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period May- Jun 01	Rank Last Period Mar- Apr 01
1	S. Yusuf, et al., "Effects of angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients," New Eng. J. Med., 342(3):145-53, 20 January 2000. [Hamilton Gen. Hosp., Ont., Canada] *275ZT	34	3
2	B. Pitt, et al., "The effect of spironolactone on morbidity and mortality in patients with severe heart failure," New Engl. J. Med., 341(10):709-17, 2 September 1999. [6 institutions worldwide] *231DB	30	4
3	H.B. Rubins, et al., "Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol," New Engl. J. Med., 341(6):410-8, 5 August 1999. [11 U.S. institutions] *223UN	30	2
4	M. Cavazzano-Calvo, "Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease," Science, 288(5466):669-72, 28 April 2000. [Hop. Necker, Paris, France; Inst. Pasteur, Paris, France] *308RR	28	†
5	S. Nishino, et al., "Hypocretin (orexin) deficiency in human narcolepsy," The Lancet, 355(9197):39-40, 1 January 2000. [Stanford U. Sch. Med., CA; Leiden U., Netherlands] *279MU	26	†
6	S. Black, et al., "Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children," Pediat. Infect. Disease J., 19(3):187-95, March 2000. [Kaiser Permanente, Oakland, CA; Wyeth Lederle Vacc. & Pediat., Pearl River, NY; U. Penn. Sch. Med., Philadelphia; Vanderbilt U., Nashville, TN] *296NF	24	10
7	T.C. Quinn, et al., "Viral load and heterosexual transmission of human immunodeficiency virus type 1," New Engl. J. Med., 342(13):921-9, 30 March 2000. [Johns Hopkins U., Baltimore, MD; NIAID, Bethesda, MD; Columbia U., New York, NY; Makerere U., Uganda] *299DC	24	†
8	A.M.J. Shapiro, et al., "Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen," New Engl. J. Med., 343(4):230-8, 27 July 2000. [U. Alberta, Edmonton, Canada] 337QC	24	†
9	D. Finzi, et al., "Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy," Nature Medicine, 5(5):512-7, May 1999. [7 U.S. institutions] *217KA	20	†
10	J.M.M. Walboomers, et al., "Human papillomavirus is a necessary cause of invasive cervical cancer worldwide," J. Pathol., 189(1):12-9, September 1999. [5 institutions worldwide] *232FM	20	†
SOURCE: ISI’s Hot Papers Database. the Legend.

he death in Philadelphia last year of a young man taking part in a trial of gene therapy will have reinforced the views of those who say that too much has been claimed too soon for these experimental treatments. A promising report (paper #4) from Dr. Alain Fischer’s group at the Necker Hospital, Paris, France, appeared on April 28, 2000, before that U.S. fatality, so it is good to see early recognition of the importance of this work, if only as a balance to some of the current gloom.

Fischer and colleagues were studying one of the severe combined immunodeficiency diseases (SCID). In public-health terms the world’s most serious immunodeficiency disease is, of course, the acquired one known as AIDS, but research on the inherited (genetic) forms is yielding both vital new information about how the immune system works and also the beginnings of novel treatments. Indeed Fischer himself has recently reviewed for a clinical journal the basic science of the almost 100 primary immunodeficiency diseases (see A. Fischer, "Primary immunodeficiency diseases: an experimental model for molecular medicine," Lancet, 357[9271]:1863-9, 9 June 2001).

Nine types of SCID have been reported. They are very rare. The type first to be studied as a candidate for gene therapy, a decade ago, was adenosine deaminase deficiency. Here gene therapy has certainly had its ups and downs. However, as Dr. W. French Anderson notes in a commentary on Fischer’s paper (see Science 288[5466]:627-9, 2000), there has been one long-term success—surprisingly in a girl given only gene-corrected mature T cells rather than stem cells which have much greater potential. The Necker Hospital group describe two patients in detail, one aged 11 months and the other 8 months, and a third treated at 1 month of age, who had an X-linked type of SCID. In SCID-X1 lymphoid progenitor cells, because of a gene defect, are unable to differentiate into the life-protecting T and NK (natural killer) cells. The X-chromosome linkage and the need for total isolation from a hostile world of infection explain the popular name for this disease, the "boy in a bubble" syndrome.

Fischer and colleagues used a defective retrovirus (Moloney) derived vector to place the needed gene into the patients’ own marrow hematopoietic cells. (Bone marrow transplantation, a realistic option in SCID, was not ideal here because no fully matched donor was available.) The early promise of the Science paper (#4) seems to have been borne out in further follow-up. Fischer now describes correction of SCID-X1 in four of five patients, and follow-up is beyond a year now in three of them. All the same he remains cautious. He tells Science Watch that "these results provide a form of proof of principle that gene therapy can work" but they do "open the door to a careful widening of applications to other SCIDs."

Mr. David W. Sharp, M.A. (Cambridge), was deputy editor of The Lancet, London, U.K., from 1976 to May, 2001; he is currently a contributing editor to that journal.