Discussion Forums > Working Towards a Cure
The Latest Update from Pat G about Gene Therapy
Andy Battaglia:
There are other gene therapy trials either ongoing or in the works. Each one is a bit different in their methods. I really wish the profit motive could be removed from this, so that these various groups would work together. Dr Sadelain is not guided by profits and has no investment in any company doing genetic research. This cannot be said of some of the others.
What I posted earlier was the latest update from Pat G. I feel that at this point he does not want to raise any false hopes about when the trials will start because there have been so many previous delays, mostly due to funding issues. I do think we will hear an announcement in the next couple months about the trials beginning.
The life expectancy of thals is still not the same as the general public, but this changes every year. A well managed treatment program is necessary.
love and prayers:
Andy i judt found this. Appearantly the first gene therapy trial has already been successful...
this is the link:
http://docs.google.com/viewer?a=v&q=cache:gIQcRs6RAlkJ:www.esh.org/ChaptersIronHB/IRON2009_CAP.15(390-401).pdf+update+of+the+first+human+trial+(Yves+Beuzard+replacing+Philippe+Lebouch,+Fontenay-aux+Roses).&hl=en&gl=uk&pid=bl&srcid=ADGEESj219CGufFePBFeW-VuQZyyomnN9a3hzjZznoks0j_ek--EFXTPNAHV6Bl35FpL00Mrw-xIhhhIHo1flEDcvE9wFnJY0O1gd9J7H2PLAz4qG4pE_7mH3JGRMDRyO_RQluuvbZIP&sig=AHIEtbSapvzEfa6sRl7F67c4sGjFobm_aQ
The first patient with severe thalassaemia who underwent a complete procedure without
injection of back-up cells was given the globin gene therapy at age 18 years. He
suffered from severe anaemia due to the bE/b0 thalassaemia genotype requiring regular
transfusions (about 160 mL of packed erythrocytes/kg/year) from the age of 3
years. Attempts to replace transfusions by hydroxycarbamide (hydroxyurea: Hydrea®)
were unsuccessful and there was no suitable familial donor for HSC transplantation.
He received 4x106 CD34+ cells/kg. Twenty months after gene therapy, the patient
did not suffer any side effects associated with the procedure as a whole. The
proportion of LG-modified blood nucleated cells rose progressively (Figure 3A) to
6% after 12 months (assuming not more than one copy of the integrated vector per
cell). The requirement for transfusion declined progressively and transfusions were
no longer necessary after 12 months. The concentration of therapeutic haemoglobin
in blood reached 2.8 g/dL (1/3 of total haemoglobin) 7 months after the last
transfusion (19 months after GT) (Figure 3B and 3C).
Anaemia was stabilised (Hb between 8 and 8.5g/dL) following transfusion but the
persistent high reticulocyte counts (not shown) indicate that the genetically
modified erythroid cells compensated only partially for the deficits of red cells and
haemoglobin. The proportion of therapeutic b-globin chain in reticulocytes was low
and variable (2-8% of total Hb). Most probably, therapeutic b-globin was distributed
among only a small proportion of reticulocytes. The large increase in the proportion
of the therapeutic Hb in blood (33% of total Hb) and the low proportion in
reticulocytes (mean 3%) suggests that the b-globin-containing reticulocytes
generated red cells with an increased survival, probably close to normal life
expectancy of healthy red cells. The abundance of foetal Hb (HbF) in reticulocytes
increased transiently following patient conditioning and decreased during the
recovery from aplasia. Before gene therapy, when the patient was hypertransfused,
the proportion of HbF in reticulocytes was 26%, rising to 57% in reticulocytes 2
months after the GT procedure and subsequently progressively decreasing around
20%, 6 months after the last transfusion and 18 months post gene therapy.
Vector-bearing cells were not uniformly distributed in all cell types: they made up
8-12% of granulocytes, 9-13% of early erythroid progenitors, 2-4% of circulating
erythroblasts, 6% of B lymphocytes and less than 1% of T lymphocytes. There
appeared to be a weak selection for modified common myeloid cells over lymphoid
progenitors; alternatively, B lymphocytes may just have a lower turnover than myeloid
cells. The low proportion of genetically modified T lymphocytes is very likely due
to the fact that cyclophosphamide was not used for conditioning. Busulphan alone
is not believed to kill T cells. The reason for the low proportion of circulating
erythroblasts carrying the vector as compared to early erythroid progenitors is not
known. Interestingly, the proportion of modified early erythroid progenitors (as
detected by PCR analysis of colonies) was similar to the proportion of colonies
producing the therapeutic haemoglobin (determined by HPLC) suggesting negligible
silencing (position effect variegation) of the therapeutic transgene, protected by
the chromatin insulator flanking the integrated vector.
At the most recent follow-up examination, blood and bone marrow cells from this
patient had normal morphology other than the thalassaemic features remaining in
a large proportion of cells. Importantly, the patient reported good wellbeing. His
life is transformed and he is free from doctors, transfusions and frequent blood tests.
He is able to perform his full time job without fatigue. Life-long follow-up with
periodic evaluation will be required to determine the stability of the corrected
phenotype, the long-term survival of repopulating HSCs and oncogenic safety.
In summary, this historical patient, who underwent ex vivo globin gene transfer for
a frequent and severe genetic disease provides the proof of principle of this
therapeutic approach. In particular, the case demonstrates that large amounts of
a therapeutic protein (b-globin) can be produced in vivo (84 g/L of red cells which
is close to the amount of globin produced by the expression of one normal
endogenous b gene) and that production can be limited to a single appropriate
lineage of cells and differentiation stage by use of a tissue specific transcription
system (erythroid promoter and globin LCR) involving a single copy of a “full” gene
(containing introns). The case also validates somatic gene transfer using a lentiviral
SIN vector with chromatin insulators for transducing long-term repopulating
haematopoietic stem cells. It demonstrates that somatic gene transfer, ex vivo, can
provide transfusion independence for a patient with severe HbE/b0 thalassaemia
disease, the most frequent b-thalassaemia genotype in the world.
For the most severe thalassaemic patients to be included in this trial, we propose
to double the proportion of transduced erythroid progenitors to 20%, so as to provide
more than 5g of therapeutic Hb/dL of blood, as this should be sufficient to improve
the b0/b0 thalassaemia major severe phenotype similar to the improvement
associated with a stable 20% chimerism provided by an allogeneic haematopoietic
transplantation (10).
i hope this is alll true!
Andy Battaglia:
This is the same company spoken about in the post at http://www.thalassemiapatientsandfriends.com/index.php?topic=3624.msg36813#msg36813 by FaReS AL BaLoShi. Yes, Dr Leboulch spoke about this at the NYC conference in October, 2009. I realize that this company has secured good funding and has been running trials, but I also did not feel that the pointed questions asked of Leboulch by Dr Sadelain at this talk, were adequately answered. There are some questions about the harshness of the methods, along with other things. Some things I have heard privately gave me added concern. I wish this company success, but I do feel we have not been given a full picture and until more is known, I will have some skepticism about this group, who are profit oriented. I truly hope the concerns can eventually be dismissed.
love and prayers:
the method may be harsh but it has been successful which is definately the best news for all thals around the world. methods get refined over a period of time and hopefully this will be available very soon for the masses.
love and prayers:
"Clonal Population of Cells Detected in a Clinical Human Gene Transfer Trial Using Lentiviral Vector
The National Institutes of Health Office of Biotechnology Activities (OBA) has been informed that a "relative clonal dominance" was detected during follow-up of a subject who is participating in a French human gene transfer trial being conducted for individuals with β-Thalassemia Major and Sickle Cell Anemia. The clinical trial, sponsored by Genetix France, used hematopoietic stem cells transduced by a self inactivating (SIN) HIV-1 lentiviral vector containing the gene for β-globin under the control of the β-globin promoter. The subject received the gene modified cells in June 2007.
This clonal dominance appears to result from the integration of the vector in the gene encoding for the HMGA2 protein, which is associated with both benign and malignant tumors. The clone however has been stable for five months and the subject remains in good health. In fact, although the subject required almost monthly blood transfusions during the 11 months prior to the gene transfer intervention, the subject has not since required a blood transfusion.
The investigators involved in this trial will be performing further studies to evaluate the consequences of this integration and its capacity to proliferate. Until these studies are completed and another review is performed by the French Medicine Agency, AFSSAPS, no other subjects in this study will receive the gene modified cells. "
i just read this as well. could you please tell me how this works. from what i understand is that although the patient was cured the process lead to the formation of a tumor which is currently stable but could be hazardous in the future. is this correct?
by the use of harsher methods did you mean that the formation of tumors as a result of gene therapy?
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