Blood, 15 February 2003, Vol. 101, No. 4, pp. 1209-1209
Gene transfer: take 5?
After years of insufficiency, we are in the process of
overcoming major hurdles to retroviral (including lentiviral) gene delivery into human hematopoietic stem cells. But with the increasing potency of the methods used, dose- finding is becoming more important. This is underlined by recent observations of serious side effects of
gene therapeutic interventions which occurred not only in a mouse model
(Li et al, Science. 2002;296:497) but also in the first really
successful clinical trial (Check, Nature. 2002;420:116-118).
As genotoxicity by random transgene uptake is a default issue of
any integrating vector technology, a thorough characterization of
insertion site frequency and locations is urgently required. The study
by Woods and colleagues (page 1284) is an important step in this
direction. They show that a subset of cultured CD34+ cells
is at increased susceptibility to lentiviral gene transfer, potentially
resulting in multiple (more than 5) vector insertions per single cell.
Some insertions may result in oncogene activation or disruption of a
tumor suppressor allele, as documented for BRCA1 in
this study. It is puzzling to note that this event was observed in an
animal with seemingly monoclonal human hematopoiesis.
These findings may catalyze a new phase in the improvement of transgene
delivery methods that does not simply focus on improving overall
efficiency. In fact, a number of preclinical studies in both
conventional retroviral and lentiviral vector development may have been
conducted under conditions of high copy number that do not appear
desirable for clinical use. To achieve a fair assessment of both
potency and side effects of genetic interventions, a new discipline is
arising that could be addressed as transgene toxicology. Now that we
have learned to open the door, it will be a challenge to define the boundaries.
Christopher Baum
Hannover Medical School; Cincinnati Children's
Hospital
