4. Discussion
Current haemophilia treatment consists of parenterally administered
plasma-derived or recombinant clotting factor concentrates.
Patients have significantly
benefited from replacement therapy, as it greatly improves their quality
of life and prolongs life-expectancy. It has been observed that the
recently introduced into the market modified release formulations which
can be applied sub-cutaneously have improved the dosing regimen for
these patients.
Although current coagulation factor replacement prophylaxis regimens are
effective, they are expensive, challenging to adhere to, result in
regular sub-therapeutic trough factor levels, and are potentially
immunogenic. As such, nearly all haemophilia patients would benefit from
an intervention that induces stable factor expression. There is the need
to develop such a therapy as the haemophilia population ages and
develops medical co-morbidities that make effective prophylaxis
administration more difficult.
In recent studies, gene therapies have induced sustained levels of FVIII
and FIX, prevented bleeding, and reduced or eliminated the use of factor
replacement products. This approach could also alleviate the heavy
burden of the need for frequent factor infusions, concerns about
inhibitor development, and limited global access to factor products.
However, while short-term risks appear to be low, it has been noted that
long-term safety and efficacy are not yet established.
Two separate AAV-based gene therapy phase 1/2 clinical trials for
haemophilia A have now reported stable FVIII levels after a single
vector dose, demonstrating that gene therapy is an effective
investigational treatment of patients with adult haemophilia A. In
haemophilia B, even though multiple phase 1/2 gene therapy clinical
trials, have now reported stable therapeutic FIX expression after a
single treatment using an AAV vector.
Some additional considerations are related to the type of vector used
(namely AAV-based or lentiviral) and their applicability in different
age groups of patients with haemophilia. Humoral immunity to wild-type
AAV represents one of the most important limitations to successful
systemic transduction with AAV vectors. Pre-existing and recall
responses to the WT virus from which the vector is engineered, or to the
transgene product, can interfere with therapeutic efficacy [30-31].
Humans are naturally infected with wild-type AAV during childhood, and
thus may develop neutralising antibodies that prevent gene transfer with
AVV vectors. Due to the high level of conservation in the amino acid
sequence among AAV capsids, anti-AAV antibodies show cross- reactivity
with multiple serotypes. This has resulted in exclusion of many patients
from recent studies. The main toxicity seen in clinical trials has been
dose-related elevation of liver transaminase following vector infusion
and, in some studies, this coincides with the demonstration of
cell-mediated AAV capsid immunity. Early intervention or prophylaxis
with corticosteroids with the aim of protecting transduced hepatocytes
have been used in most studies, but not all episodes have been managed
effectively and partial/complete loss of transgene expression occurred.
Pre-existing AAV humoral immunity and the potential loss of vector
transduction with time represent important and limiting issues in the
AAV-based gene therapy and can render the therapy ineffective. Thus,
there is a requirement for other viral and non-viral-based vectors for
transgene delivery. The predominant methods studied in Haemophilia have
used lentiviral vectors, for which there is a lower incidence of
pre-existing humoral immunity and which have a greater packaging
capacity than AAV vectors.
A specific concern is the application of gene therapies in children. It
is still unclear how effective AAV gene therapy will be in young
children lacking data on long term exposure, particularly in terms of
the risk for inhibitor and potential loss of factor expression over time
as a result of dilution of AAV-transduced hepatocytes during liver
growth [5]. Integrating Lentiviral Vector may provide an alternative
vector platform for treating children with haemophilia with in vivo
liver gene delivery of immune stealth and tolerogenic LV vectors to
hepatocytes. In children and adults with either high-risk mutations for
inhibitors, history of inhibitor, or presently with inhibitor, it is
unclear whether the robust AAV mediated liver tolerance and ITI observed
in haemophilia animal models will translate in humans [5].
Lentiviral vectors (LV) potentially offer certain advantages. They are
able to efficiently integrate into the target genome, even when the
cells are not actively dividing. If the liver is the target organ, this
can lead to transduction of nondividing hepatocytes with the potential
of long-term transgene expression. The liver also contains an abundance
of antigen-presenting cells (APCs) that can also be transduced.
Transduction of APCs might increase the risk of an immune response to
FVIII or FIX and thereby inhibit long-term expression. The use of
hepatocyte-specific promoters and incorporation of
hematopoietic-specific microRNA target sequences into the vector may
reduce this immune risk.
Another point of discussion is the external validity of the results
obtained from the clinical trials with a selected patient population.
Although the clinical data supporting gene therapy for haemophilia have
been rather positive, the enrolled subjects bias are a selected group,
and thus some caution is advised in extending the benefits of gene
therapy to the general population of patients with haemophilia due to
potential selection bias of the results from the clinical studies.
Finally, the many factors playing a role in the decision-making process
for patients with haemophilia need to be considered carefully. Despite
some very promising data provided on the novel treatments for
haemophilia A and B, patients still have needs that require
clarifications in consideration of the impact that these new therapies
can have on their lives. The use of Emicizumab in Haemophilia A patients
with inhibitors constitutes a remarkable achievement as this novel
medicine, approved in EU on January 2018, allow the patients to have one
subcutaneous administration per week, rather than one every 2/3 days.
This is a great improvement in the treatment of Haemophilia A,
especially in terms of QoL, but there’s still the need to know how and
when it will be possible to switch the patients with inhibitors to this
novel approach. Gene therapies using the AAVs look very promising in
reducing the need for replacement therapy very close to 0 as the ABR as
well. But in this context, patients still have some concerns that need
to be elucidated, particularly many unanswered questions about the AAVs,
the increase of the liver enzymes level and hepatotoxicity, the
reduction in the FVIII expression during the time and the possibility to
be re-treated with the vector if a drop in the FVIII expression occurs.
Further, some ethical considerations have to be done concerning the use
of gene therapies in children. The hot topic for the patients’ community
is the current lack of long-term data on the treatment use of gene
replacement and splicing therapies. The latter is an urgent challenge to
be addressed in the upcoming months in order to allow haemophilia
patients to be much more aware about the therapeutic options available
for the whole community. Considering 1 million persons with haemophilia
worldwide, of whom about 418 000 have severe and mostly undiagnosed
disease, this constitutes a challenging task for researchers and health
care systems, especially because only 210,000 patients have been
identified and reported globally (WHF report 2018). More efficient
diagnostic approaches are needed in less developed countries to take
advantage of current and future treatment modalities, including gene
therapy.