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.