Download Merry Christmas for Patients with Hemophilia B

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Merry Christmas for Patients with Hemophilia B
Katherine P. Ponder, M.D.
Hemophilia B (also known as Christmas disease)
is due to deficiency of coagulation factor IX (FIX).
In this issue of the Journal, Nathwani et al. report
the first unequivocal evidence of successful gene
therapy for hemophilia B — a major advance in
this field.1 This success for hemophilia may translate into gene therapy for other blood protein deficiencies.
Hemophilia is due to deficiency in a coagulation factor and results in a bleeding disorder
that often involves joints and muscles. The most
common types are hemophilia A and B, which
are due to deficiencies of factor VIII and FIX,
respectively, and show X-linked inheritance. The
first written account of hemophilia was in the
2nd century in the Babylonian Talmud, when
Rabbi Judah decreed, “If she circumcised her
first child and he died, and a second one also
died, she must not circumcise her third child.”2
The first reported case of hemophilia due to
FIX deficiency was in 1952 and was called
“Christmas disease” after the patient, a 10-yearold boy named Stephen Christmas.3 Queen Victoria of the United Kingdom (1819–1901) was
the most famous carrier of the hemophilia B
gene. Although the protein and the gene were
not known during her lifetime or the lifetimes
of her affected male progeny (members of the
royal families of the United Kingdom, Spain,
Germany, and Russia), recent analysis of polymerase-chain-reaction assays of bones exhumed
from the graves of Czar Nicholas II and his
family showed that the FIX gene was mutated in
his son Alexei Romanov, who had hemophilia.4
At least nine sons, grandsons, or great-grandsons
of Queen Victoria were affected with hemophilia
B, and the average age at death was 24 years.
FIX concentrates were first used in the late
1960s to treat patients with hemophilia B, and
their routine use for bleeding episodes increased
the median lifespan to 63 years.5 Although enthusiasm for protein therapy was temporarily
dampened by the HIV epidemic in the early
1980s, improved methods for producing FIX have
increased its safety. Recently, implementation of
prophylactic rather than on-demand treatment
has reduced the risk of crippling joint disease.6
With the success of protein therapy, why would
gene therapy be needed? In the United States and
other developed countries, annual costs for a single adult patient of clotting factors for hemophilia are approximately $150,000 for on-demand
therapy and $300,000 for prophylaxis,6 which
could incur a lifetime cost of over $20 million.
In developing countries, prophylactic and frequent
on-demand therapy is not affordable, and patients
still have chronic joint disease and die young.7
Nathwani et al. report the truly remarkable
finding that a single intravenous injection of an
adenovirus-associated virus (AAV) vector that expresses FIX can successfully treat patients with
hemophilia B for more than a year.1 AAV is a
small (4.8 kb), nonpathogenic, single-stranded
DNA virus from the parvovirus family. The vector was generated by replacing the coding sequence for the cap and rep genes of the virus
with a liver-specific promoter and the FIX coding sequence. The vector was packaged in cells
that express cap and rep from a different piece of
DNA that does not enter viral particles, thus generating a replication-incompetent vector that cannot propagate after gene transfer. Preclinical
studies had shown that AAV vectors could be
expressed from liver in large animals for at least
10.1056/nejme1111138 nejm.org
The New England Journal of Medicine
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1
editorial
10 years.8 In this study, patients were treated
with an AAV vector that used the capsid protein
from serotype 8 (AAV8). Two patients received
2×1011 viral particles per kilogram of body weight
and achieved about 1% of normal FIX activity,
two patients received a threefold higher dose
and achieved about 2.5% of normal activity, and
two patients received a 10-fold higher dose and
achieved about 7% of normal activity. Expression has been seen for over 6 months in all patients, and prophylactic use of factor concentrate
has either been eliminated or reduced. Since the
vector is estimated to cost $30,000 per patient,
dramatic cost savings have already been achieved.
Should the practicing hematologist rush to
order this gene therapy vector if it is approved
by the Food and Drug Administration? The answer is probably yes, but the risks of this procedure are not yet totally clear. In one patient in
this AAV8 trial, alanine aminotransferase levels
were found to be about five times the upper
limit of normal at 2 months after gene therapy,
and there was in vitro evidence of cytotoxic T lymphocytes (CTLs) that reacted with epitopes of the
AAV8 capsid protein. Prednisolone therapy resulted in normalization of the liver enzyme level
within a month, and FIX expression at 6 months
was 3% of normal, which was 30% of the peak
FIX activity seen shortly after gene therapy. A
somewhat similar result was seen in a previous
trial of hemophilia B gene therapy with an AAV2
vector, in which an increase in liver enzyme levels was associated with the generation of CTLs
specific for the AAV2 capsid protein.9 However,
this patient completely lost FIX expression, leading the investigators to conclude that the CTL
response destroyed all transduced liver cells. The
finding that the CTL response eliminated transduced cells and gene expression in the AAV2 but
not in the AAV8 trial may be related to the glucocorticoid therapy used in the latter study. Alternatively, the more rapid uncoating of AAV8 than
of AAV2 capsid proteins from viral particles10
may allow the AAV8 capsid proteins to be degraded by most transduced cells before the immune system can find and destroy them. These
2
results raise the concern that patients with a
more recent immunologic memory of the AAV8
capsid may develop a fulminant hepatitis.
In sum, this gene therapy trial with an AAV8
vector for hemophilia B is truly a landmark
study, since it is the first to achieve long-term
expression of a blood protein at therapeutically
relevant levels. If further studies determine that
this approach is safe, it may replace the cumbersome and expensive protein therapy currently
used for patients with hemophilia B. This technology may soon translate into applications for
other disorders, such as lysosomal storage diseases, alpha1-antitrypsin deficiency, and hyperlipidemias.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
From the Departments of Internal Medicine and Biochemistry
and Molecular Biophysics, Washington University School of
Medicine, St. Louis.
This article (10.1056/NEJMe1111138) was published on December 10, 2011, at NEJM.org.
1. Nathwani AC, Tuddenham EGD, Rangarajan S, et al. Adeno-
virus-associated virus vector–mediated gene transfer in hemophilia B. N Engl J Med 2011. DOI: 10.1056/NEJMoa1108046.
2. Rosner F. Hemophilia in the Talmud and rabbinic writings.
Ann Intern Med 1969;70:833-7.
3. Biggs R, Douglas AS, MacFarlane RG, Dacie JV, Pitney WR.
Christmas disease: a condition previously mistaken for haemophilia. Br Med J 1952;2:1378-82.
4. Rogaev EI, Grigorenko AP, Faskhutdinova G, Kittler EL, Moliaka YK. Genotype analysis identifies the cause of the “royal
disease.” Science 2009;326:817.
5. Darby SC, Kan SW, Spooner RJ, et al. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B
in the United Kingdom who were not infected with HIV. Blood
2007;110:815-25.
6. Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys
with severe hemophilia. N Engl J Med 2007;357:535-44.
7. Ponder KP, Srivastava A. Walk a mile in the moccasins of
people with haemophilia. Haemophilia 2008;14:618-20.
8. Niemeyer GP, Herzog RW, Mount J, et al. Long-term correction of inhibitor-prone hemophilia B dogs treated with liverdirected AAV2-mediated factor IX gene therapy. Blood 2009;113:
797-806.
9. Manno CS, Pierce GF, Arruda VR, et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 2006;12:342-7.
10. Thomas CE, Storm TA, Huang Z, Kay MA. Rapid uncoating
of vector genomes is the key to efficient liver transduction with
pseudotyped adeno-associated virus vectors. J Virol 2004;78:311022.
Copyright © 2011 Massachusetts Medical Society.
10.1056/nejme1111138 nejm.org
The New England Journal of Medicine
Downloaded from nejm.org by tina tian on December 12, 2011. For personal use only. No other uses without permission.
From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved.