Serious adverse events in some human gene therapy clinical trials have raised safety concerns when retroviral or lentiviral vectors are used for gene transfer. We evaluated the potential for generating replication-competent retrovirus (RCR) and assessed the risk of occurrence of adverse events in an in vivo system. Human hematopoietic stem and progenitor cells (HSCs) and mesenchymal stem cells (MSCs) transduced with two different Moloney murine leukemia virus (MoMuLV)-based vectors were cotransplanted into a total of 481 immune-deficient mice (that are unable to reject cells that become transformed), and the animals were monitored for 18 months . Animals with any signs of illness were immediately killed, autopsied, and subjected to a range of biosafety studies. There was no detectable evidence of insertional mutagenesis leading to human leukemias or solid tumors in the 18 months during which the animals were studied . In 117 serum samples analyzed by vector rescue assay there was no detectable RCR. An additional 149 mice received HSCs transduced with lentiviral vectors, and were followed for 2–6 months. No vector-associated adverse events were observed, and none of the mice had detectable human immunodeficiency virus (HIV) p24 antigen in their sera. Our in vivo system, therefore, helps to provide an assessment of the risks involved when retroviral or lentiviral vectors are considered for use in clinical gene therapy applications.

For me it’s shows again how results of preclinical testing could be different between species and animal models. Again, even so, we never know what we will get in human when we will start a clinical trial.

Several years ago, patient deaths in gene therapy trials caused the FDA to halt all such trials under its jurisdiction, another consultant told me, and that field has never recovered.

Few protocols in parallel - good approach:
non-viral gene delivery?
other HSC expander?
small molecules?
going to read this

I don’t know about others but I learned a few things from this work,
for example I wouldn’t try to use HOXB4 as an therapeutic agent in human

Another solution is to use an inducible form of transgene. I don’t know this so correct me if I am wrong. However, I don’t seem to understand why people do not consider an inducible form of promoter when introducing a gene. For example, doxicycline inducible promoter can be used to introduce it along with a transgene of interest so that only patients who are taking doxicycline can express this transgene. If this turns out to be dangerous, patients stop taking it so that transgene is not expressed anymore. Also, transgene can be ‘floxed’ so that cre can be used in an emergency situation to remove transgene from the body.

If a therapeutic method is potentially dangerous, one should either ditch it, or find a way to neutralize the danger. And do something about it. Simple is that.

so conclusion 1: HOXB4 is not that safe what was considered before

Quote 1:

It has been demonstrated that high-level HOXB4 expression, achieved with retroviral (5) or adenoviral (15) vectors in human CD34+ cells, perturbed the myeloid differentiation program both in vitro (5, 15) an in vivo (5) without frank leukemia.

so = controversy 1

conclusion 2:

This study underscores the importance of large animal models in further development of gene and other novel HSPC-directed therapies.

Even we got to know about adverse effect of retrovirus-based gene therapy from human trials (unfortunately), this work has a great impact to the gene/cell therapy field.

It was long-term work and done during last 3 years.
I’d definitely allow to publish this in the journal of JCI level.

Actually, if you look at back to history of clinical trials, it’s a usual thing when after start of trials (which have a rational - excellent preclinical data and FDA approval), adverse effects come up later.
That’s what we see now in gene therapy and in cell (stem cell) therapy as well.

But this is a thing about trials: we don’t know how it’s will going in human! This is experiment, even after FDA approval and safety tests.

Other side of coin - desperation of patients, who will sign of participation list agreement in any trial, because they have no choice (only experimantal new treatment) and rush of researchers and clinicians in the same time.

I’d agree with Cynthia Dunbar, that frequently we are too eager to jump to clinic. We have to be more careful about new methods. Translation to clinic is always hard.