Fanconi Anemia . . .

Gene Therapy

What is Gene Therapy?

The concept of gene therapy is quite simple.  For a genetic disease caused by a single gene, you insert a corrected copy of the gene (a "therapeutic gene") into the genome of the patient.  Note that the diseased genes (each person has two copies, after all, and they both have to be pathogenic to cause disease) are left in place--the new gene is typically inserted in a random position in the patient's genome--although some gene therapy researches are working on a technology which does actually replace the pathogenic genes with a therapeutic gene. The new, therapeutic gene is then expressed by the cells and produces the functional proteins needed to cure the genetic disease. How do you get a therapeutic gene into a cell?  Typically a virus is used--viruses, after all, have evolved to enter our cells and have their genes expressed. A class of viruses, called retroviruses, can copy their genetic information into the host cell. This is exactly what is needed!  Hence retroviruses are frequently the vector (the means by which genes are inserted) used in gene therapy--this incluces modified versions of the HIV virus. Of course, the viruses have all of their disease causing genes removed from them before being used in gene therapy.

These modified viruses are typically used to infect stem cells.  Stem cells have the special property of being able to differentiate into many other kinds of cells. For Fanconi Anemia, the stem cells we are interested in would be those called hematopoietic stem cells--those stem cells that can differentiate into all the blood cell types (red cells, white cells, etc).  So the actual procedure for gene therapy is to extract stem cells from the patient, infect those stem cells with the virus vector, then re-infuse those stem cells into the patient.  Those stem cells will then grow and differentiate into all of the other cell types--each carrying a copy of the therapeutic gene.

So what can go wrong? First, the rate of infection of the stem cells may not be very high--so you only end up with a few stem cells with the therapeutic gene. The therapeutic gene may only be expressed by the cells for a short time before being shut down. The stem cells may not make a significant contribution to the total cells needed to correct the disease. Solving these problems are active areas of research for many single gene diseases.

There is also some research going on to develop technologies for inserting entire exons. This might be useful for repairing deletions in the genes.  See this report.

A Gene Therapy Success

In 2000, Alain Fischer and Marina Cavazzana-Calvo at the Necker Hospital in Paris used gene therapy to cure two children of Severe Combined Immunodeficiency Disease (SCID).   By 2002, they had treated an additional 8 children (total of 10).

SCID is a rare group of conditions in which a person's immune system doesn't develop properly. SCID is often referred to as the "bubble boy" disease, as the children have to be maintained in sterile conditions to avoid catching life-threatening infections.  SCID is a single gene disorder like Fanconi Anemia. SCID can be inherited autosomal recessive (like Fanconi Anemia) or be X-linked (inherited with the X-chromosome, so it affects only boys).

Here is a link to a BBC story of a child cured in Britain of SCID using gene therapy in 2002.

SCID Gene Therapy Concern

In October 2002, the French researchers reported that during a routine check of one of their patients, they detected abnormally high levels of a certain T cell (a type of immune system cell) in the patient.  Molecular studies revealed that all the T cells contained a DNA signature from the site where the retrovirus vector had integrated itself into the host's genome. This site is within the coding region of a gene that's "aberrantly expressed" in a form of childhood leukemia.  In short, the retrovirus used to carry the corrective gene into the patient's cells had inserted the gene in the middle of a gene known to cause leukemia.  This caused a unique form of leukemia in this patient.  The gene involved is LMO2, and the DNA from the retroviral vector was inserted between exons 1 and 2 of LMO2.

This was always thought to be a small risk--gene therapy causing cancer due to the genes being inserted in the middle of other genes that can cause cancer.

Research in the U.S. using retrovirus vectors was immediately put on hold.  An advisory panel met in October and recommended that the halt be lifted, since the risk is unclear, but the benefits can be enormous. The panel asked for changes in monitoring plans and informed consent documents.

Here is a link to an article in Science regarding this development. You may need a subscription to Science to view this article.  Otherwise, the article citation is: Science, October 18, 2002; volume 298, pages 510-511 (in News of the Week). 

Update 13 December 2002: Another article in Science regarding the SCID gene therapy cancer case. To quote, "The cancer that appeared earlier this year in a patient who took part in a French gene therapy trial appears to have been caused by a rare combination of factors, a panel of experts concluded at a meeting last week. The risk of a second occurrance seems sufficiently remove, the panel agreed, that this trial and others like it should go forward."  The review was by the National Institute of Health's (NIH's) Recombinant DNA Advisory Committee (RAC).  The patient also had another chromosomal anomaly, a copy of part of chromsome 6 attached to chromosome 13 (a 6;13 translocation), and the patient's extended family had unusual occurances of two cases of a particular childhood cancer. "This led many of the 17 RAC panelists to conclude that this predisposition and other factors, possibily involving the 6;13 translocation, worked in concert with the LMO2 insertion to produce leukemia."  The RAC concluded that other gene therapy trials should proceed, but they recommended that federal guidelines be revised to suggest to gene-therapy researchers do more intensive monitoring for signs of cancer and archive tissue so that molecular events can be traced. The RAC is scheduled to vote on further recommendations in March 2003, when "it will expand the discussion to other gene-therapy studies that use retroviruses." The article citation is: Science, December 13, 2002; volume 298, No. 5601, pages 2113, 2115.

Update 14 January 2003: The French researchers have reported a second case of leukemia from their SCID gene therapy patients. The FDA has put gene therapy trials using retroviruses on hold again. A meeting is to be held by the NIH's RAC committee on 17 January 2003 to review the clinical data and weight next steps. See this news item at Science NOW and this press release from the American Society of Gene Therapy (ASGT) (and other ASGT press releases).See this Fact Sheet from the RAC (pdf format).

Update 14 February 2003: An emergency meeting of the RAC this week brought the bad news that a third child has T cells with the same gene insertion near LMO2, although this child does not have leukemia. The RAC has concluded that the leukemia was not a random event but instead constitutes a serious inherent risk. They are still thinking that some gene therapy trials may go forward, as the risk may be justified based on the disease being treated (for example, adults threatened by solid tumors, children with SCID who have failed standard transplant therapy). The RAC will meet again on February 28 to review additional data from the French trial.  See another two articles in Science: January 24, 2003 p. 495 and February 14, 2003 p. 991

Update 7 March 2003: An sort news item in Science saying that the RAC met last week and recommended that the FDA allow most U.S. gene-therapy studies to proceed. The panel believe that the therapy caused the cancer, but they concluded that most of the suspended studies should resume. They did back a 2-year delay of three trials that are similar to the French study, unless sponsors can show there are no alternatives.

Update 3 June 2003: See this conference report at Medscape.com on "Severe Immunodeficiencies: Bone Marrow Transplantation or Gene Therapy?"

Update 13 June 2003: See this short article on how the use of the murine leukemia vector (MLV) is riskier than expected. See the original NIH News Release.

Update 18 Feb 2005: A third child in the French X-SCID gene therapy trial has developed leukemia (reported on 24 Jan 2005). One of the original two children died last October. The French trial has been halted again and the FDA has suspended three U.S. SCID trials, but a trail in Britain continues. Experts are expected to discuss the case in March at NIH's Recombinant DNA Advisory Committee. (Reported in Science, vol. 307, 18 Feb 2005, pg. 1028).

Additional Gene Therapy Overview Information

Follow this link for a lot more information on gene therapy

Appendix L of Fanconi Anemia - A Handbook for Families and Their Physicians has an overview of gene therapy written by Dr. Christopher Walsh, MD, PhD, of the University of North Carolina (Chapel Hill).  He's running the second gene therapy trial listed below.

Fanconi Anemia Gene Therapy Trials

Here is a story from the July 12, 1999 Business Week that mentions briefly the work of Dr. Liu (plus quite a bit about the Frohnmayer family).

Here is an abstract from April 15, 1995 on Dr. Liu's research in mice and here is the full research article (pdf format). From the NIH protocol number, we can tell than the study was approved in 1994. I have not be able to find recent information about it.

Johnson Liu, M.D.
Hematology Branch, DIR
National Heart, Lung, and Blood Institute
Building 10, Room 75213
Bethesda, MD 20892
Ph: 301-496-2452
Fax: 301-496-8396
Email:

The Fall 2002 Science Letter (No. 32) of the Fanconi Anemia Research Fund had a good summary of the gene therapy research being done by Christopher Walsh, MD, PhD, at the University of North Carolina, Chapel Hill.   You should read the entire article, but I will summarize it briefly here.  So far they have had 4 patients enroll in their current gene therapy trial, which uses a retrovirus to insert a normal FANCA gene into blood-forming stem cells.  One patient had a significant increase in peripheral blood cells carrying the FANCA gene and stabilizing blood counts.  They have learned from the four patients that FA patients have fewer (10-100 time fewer) blood-forming stem cells than the normal population.   To improve gene therapy for FA patients, then, they need to increase the number of stem cells harvested and increase the efficiency of gene transfer into the stem cells.   To increase the number of stem cells, they are working on identifying and isolating new cell types that function as blood-forming stem cells.  To increase the efficiency of getting the normal FANCA gene into these stem cells, they are exploring a the use of a new virus, a lentivirus, derived from HIV-1.  This modified virus has shown superior effectiveness in transferring genes into cells (and was used in the successful SCID cases).  A new trial will be initiated in the future that uses this lentiviral approach.

Dr. Christopher Walsh
UNC Gene Therapy Center
Room 7101, Thurston Bldg.
CB#7352
Chapel Hill, NC  27599
Phone (919) 966-9116
FAX   (919) 966-0907
Email:

This study kicked off in 1998.  This study was mentioned in Family Newsletter 23 (February, 1998) of the Fanconi Anemia Research Fund.  I have not been able to find more recent information about it, although from the NIH protocol number, this protocol was approved in the year 2000.

Links to news of this study:

• $4.7 Million To Support Gene Therapy Research ... IU School of Medicine
• D. Wade Clapp, M.D.  another link

Other Studies

In my web searches, I've come across other studies that I will list here.  These studies typically occurred in the past.

Gene Therapy for the Treatment of Fanconi's Anemia Type C

Phase I Pilot Study of CD34 Enriched, Fanconi's Anemia Complementation Group C Gene Transduced Autologous Peripheral Blood Stem Cell Transplantation in Patients With Fanconi's Anemia

Orchard, Paul J., University of Minnesota Medical School, Minneapolis, Minnesota; Transplantation of Unrelated or Mismatched Related Donor T Cells Containing the HSV-TK Suicide Gene to Facilitate Engraftment and Control Graft-Versus-Host Disease in Patients with Fanconi Anemia. A Phase I Trial. NIH 0203-520 (Open)

Non-Viral Gene Therapy for Fanconi Anemia. Principle investigator Markus Grompe, M.D., Oregon Health & Science University, Portland, OR.

Gene Therapy for Fanconi Anemia using Lentiviral Vectors. Principle Investigator Inder Verma, Ph.D., Salk Institute for Biological Studies, La Jolla, CA. Journal article in Blood. Article in BusinessWeek

You can find other clinical trials (not all involving gene therapy) for Fanconi Anemia by searching at the ClinicalTrials.gov website. You can also search federally funded research using the CRISP database (go to the search page and search for the phrase "Fanconi Anemia")..

Gene Therapy Links

• American Society of Gene Therapy
• European Society of Gene Therapy
• Office of Biotechnology Activities
  • Home of the Recombinant DNA Advisory Committee (RAC)
  • Can search for specific trials at this site:
    • click on "Protocol List and Other Documents"
    • then click on "Protocol List" (pdf file)
    • then you can search use the search function in Adobe acrobat reader

• Human Genone Project Information - Gene Therapy.  This site has many more links to articles about gene therapy and other gene therapy links. Recommended!

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Last Updated: 27 Feb 2005