Gene therapy

 Short-lived nature of gene therapy – Before gene

therapy can become a permanent cure for any
condition, the therapeutic DNA introduced into
target cells must remain functional and the cells
containing the therapeutic DNA must be long-
lived and stable.
 Problems with integrating therapeutic DNA into
the genome and the rapidly dividing nature of
many cells prevent gene therapy from achieving
any long-term benefits.
 Patients will have to undergo multiple rounds of
gene therapy.
 Immune response – Any time a foreign object
is introduced into human tissues, the immune
system is stimulated to attack the invader.
 The risk of stimulating the immune system in
a way that reduces gene therapy
effectiveness is always a possibility.
 Furthermore, the immune system's enhanced
response to invaders that it has seen before
makes it difficult for gene therapy to be
repeated in patients.
 Problems with viral vectors – Viruses, the
carrier of choice in most gene therapy
studies, present a variety of potential
problems to the patient:
 toxicity, immune and inflammatory
responses, and gene control and targeting
issues.
 In addition, there is always the fear that the
viral vector, once inside the patient, may
recover its ability to cause disease.
 Multigene disorders – Conditions or disorders
that arise from mutations in a single gene are the
best candidates for gene therapy.
 Unfortunately, some of the most commonly
occurring disorders, such as heart disease, high
blood pressure, Alzheimer's disease, arthritis,
and diabetes, are caused by the combined
effects of variations in many genes.
 Multigene or multifactorial disorders such as
these would be especially difficult to treat
effectively using gene therapy
 For countries in which germ-line gene
therapy is illegal, indications that
the Weismann barrier (between soma and
germ-line) can be breached are relevant;
spread to the testes, therefore could impact
the germline against the intentions of the
therapy.
 Chance of inducing a tumor (insertional mutagenesis) – If
the DNA is integrated in the wrong place in the genome,
for example in a tumor suppressor gene, it could induce a
tumor.
 This has occurred in clinical trials for X-linked severe
combined immunodeficiency (X-SCID) patients, in which
hematopoietic stem cells were transduced with a corrective
transgene using a retrovirus, and this led to the
development of T cell leukemia in 3 of 20 patients.
 One possible solution for this is to add a functional tumor
suppressor gene onto the DNA to be integrated; however,
this poses its own problems, since the longer the DNA is,
the harder it is to integrate it efficiently into cell genomes
 The cost - only a small number of patients can
be treated with gene therapy because of the
extremely high cost (Alipogene tiparvovec or
Glybera, for example, at a cost of $1.6 million
per patient was reported in 2013 to be the
most expensive drug in the world)
2014
 In January 2014, researchers at the University of
Oxford reported that six people suffering
from choroideremia had been treated with a genetically
engineered adeno-associated virus with a copy of a
gene REP1.
 Over a six month to two year period all had improved their sight.
Choroideremia is an inherited genetic eye disease for which in the
past there has been no treatment and patients eventually go
blind.
 In March 2014 researchers at the University of
Pennsylvania reported that 12 patients with HIV had been
treated since 2009 in a trial with a genetically engineered
virus with a rare mutation known to protect against HIV
(CCR5 deficiency). Results were promising
 Sixty years ago, the question was: what does our
genetic code look like? Then: how many genes
make up our DNA? After that: which genes cause
diseases?
 Now the question is: what if we could repair
broken genes?
 It has been a goal of doctors and scientists for
decades to correct disease-causing mistakes in
our DNA. A new technology called genome
editing brings us closer to making that goal a
reality.
 Today we know that there are over 5,000 genes that cause genetic diseases, the majority of which have no cure or
treatments. These are the diseases that stand to benefit most from genomic medicine and, specifically, the newest
and most powerful genome-editing technology called CRISPR (pronounced “crisper”).
 We hope that many severe and life-threatening diseases can be treated by technologies such as CRISPR: diseases
such as cystic fibrosis, which attacks the lungs and digestive system; Duchenne muscular dystrophy (DMD), a
muscle disease; and sickle cell disease, a debilitating blood disorder.
 By “correcting” genetic defects in patients with these diseases, we hope to restore the normal function of the gene
and significantly improve quality of life. For patients with DMD, this could mean being able to walk and breathe
better; for patients with cystic fibrosis, this could mean breathing more easily; and for patients with sickle cell
disease, this could mean reducing the painful crises caused by the disease.
 CRISPR has taken the scientific research community by storm because it is easy to use and it can make DNA
changes in many different settings and many different kinds of cells. Scientists can now investigate what different
genes do and how they work together much more rapidly and comprehensively.
 CRISPR relies on a programmable molecular machine (an enzyme) called Cas9 that binds to a small-guide RNA
molecule. Together, these components home in on the target gene and carry out precise molecular “surgery” to
create a genetic change. This can be used to correct a defect that causes a genetic disease. The technology is
young, and it will take time to fully realize this promise. Some diseases will be more challenging than others, and
there is a lot of work to be done to further extend CRISPR’s capabilities.
 However, we are at a watershed moment in our understanding of genomic science. Not only have we identified
many of the mutations that cause a variety of diseases but we have also identified a technology with the potential
to create novel medicines that directly target and correct those mutations.
 This is just one of the many areas we are exploring at Editas. We believe we have the opportunity to unlock a broad
class of new transformative genomic medicines that will enable precise, corrective modifications to DNA to treat
the underlying causes of genetic diseases. More importantly, we’re getting closer to making once untreatable
conditions treatable by repairing broken genes.