FEATURE
Breakthroughs in Gene
Therapy for Hemophilia
Gene therapy for hemophilia is here – and it’s working. The field is advancing at a steady clip: Results from recent trials of this
revolutionary approach have restored patients’ anticoagulant factor activity levels to normal or near-normal levels and reduced
patients’ annualized bleeding rates by nearly 90 percent.
A handful of candidate products are being evaluated in phase III studies of patients with hemophilia, and several more are in
early development, but questions about their long-term safety and efficacy remain.
“With gene therapy, the goal is to provide a single intervention that will have a long-lasting effect and free people from
the need for chronic administration of medicine,” according to Katherine A. High, MD, a hematologist and president and head
of research and development at Spark Therapeutics, a Philadelphia-based biomedical company that focuses on gene therapy
products for inherited disorders like hemophilia.
ASH Clinical News spoke with Dr. High and other hemophilia specialists to better understand the details of this revolutionary
new treatment and to get an update on the race to a “cure” for hemophilia.
A One-and-Done Treatment?
The typical treatment of hemophilia entails frequent intrave-
nous infusions of the missing coagulation protein to either treat
or prevent bleeding episodes. The need for weekly (or more
frequent) administration of recombinant factor VIII (FVIII) or
factor IX (FIX) replacement is costly, burdensome, and com-
plicated. And, with only about 25 to 30 percent of the world’s
hemophilia population having full access to factor replacement,
the promise of a gene therapy solution for hemophilia offers
hope for more global access to treatment.
Gene therapy is designed to provide long-term expression
of the missing or abnormal coagulation factor at sufficient and
steady enough levels to reduce – or even eliminate – the need
for exogenous factor replacement. A number of different gene
delivery vehicles have been tested, but all the therapies now in
advanced development use a recombinant adeno-associated
virus (rAAV) vector to deliver the coagulation factor gene to a
patient’s liver.
AAV is a versatile viral vector technology discovered more
than 50 years ago that can be engineered for very specific
functionality in gene therapy applications. 1 The rAAV vectors
lack viral DNA and essentially are protein-based nanoparticles
engineered to traverse the cell membrane and deliver their gene
of interest into the cell nucleus.
As Dr. High explained, gene therapies are designed to be
single-dose treatments with potentially curative results. As far
as whether gene therapy will really offer a “cure,” John Pasi,
MBChB, PhD, Hemophilia Centre Director at Barts and The
London School of Medicine and Dentistry, is hesitant to use
that word.
“Cure is a word we use with considerable caution,” said
Dr. Pasi, who is the principal investigator on trials evaluating
valoctocogene roxaparvovec, BioMarin Pharmaceutical’s gene
therapy product for hemophilia A. “We don’t know how long
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Focus on Classical Hematology
gene therapy will last yet, but we may be looking at a treatment
that can massively reduce the treatment burden and substan-
tially improve quality-of-life for men with severe hemophilia,”
he added.
Also, this treatment only affects the patient living with
hemophilia; since the genetic mutation remains, hemophiliacs
can still pass the disorder to their offspring.
Lindsey A. George, MD, another gene therapy researcher
and an attending hematologist at Children’s Hospital of Phil-
adelphia, is also reluctant to call gene therapy a cure, but said
the clinical trial results are often profound and life-changing
for participants.
“What we can say is that these patients are not requiring
factor replacement for extended periods of time, they’re not
having breakthrough bleeds, and their lives are no longer
dictated by hemophilia – all of which is consistent with a cure,”
Dr. George said.
Indeed, many of her patients have expressed a newfound
sense of freedom after receiving gene therapy, including a
noticeable uptick in their activity levels.
The Race Is On!
Hemophilia B, despite being far less common than hemophilia
A, was initially a more attractive target for gene therapy from a
molecular perspective.
“Typically, the diseases are identical and, in both, only a
modest amount of expression is required to produce a big ben-
efit for the patient,” Dr. George explained. “But, the FVIII gene
is much bigger than the FIX gene and the packaging capacity
of an AAV vector (in other words, how much DNA can be fit
in) is smaller than the FVIII gene itself.” Researchers needed
extra years, even decades, to figure out how to package the
FVIII gene into an AAV vector, which involved bioengineer-
ing smaller promoters and coding for a truncated (B domain