Italian Gene Therapy Success – Thanks to Animal Research

Italian scientists announced yesterday that they had successfully treated the deadly genetic disorders metachromatic leukodystrophy and Wiskott-Aldrich syndrome in a small clinical trial, marking and another major landmark in the developing field of gene therapy. As you might expect the breakthrough has received widespread media coverage, including CBS, the BBC and the Italian edition of the Huffington Post. While these reports do a reasonable job of explaining the significance of these two small trials, they do miss out one important fact, that this advance rests on many years of basic and applied scientific research, much of which required animal studies.

Many of the reports highlight the fact that this trial – led by  Dr Luigi Naldini, Dr Alessandra Biffi and Dr Alessandro Aiuti of the San Raffaele Telethon Institute for Gene Therapy – involved the use of parts of HIV virus to create a vector that can then insert function versions of the genes that are missing or defective into bone marrow stem cells of the patients, before transplanting the corrected cells back into the patients. This utilisation of a deadly virus to create a therapy that saves lives still takes people by surprise, but really it should not as this is not the first time. Last year we discussed on this blog how such a lentiviral vector had been used to successfully treat acute lymphoblastic leukemia while back in 2009 we saw how a similar gene therapy vector was used to treat the neurological disorder cerebral X-linked adrenoleukodystrophy (X-ALD). Animal research made crucial contributions to these two therapies, and it wasn’t surprising to find that it played an equally crucial role in developing gene therapy for metachromatic leukodystrophy and Wiskott-Aldrich syndrome.

In the paper published online in Science (1) reporting on the outcome of the trial of gene therapy in 3 boys with Wiskott-Aldrich Syndrome (WAS) , the Telethon team write that:

We developed a SIN lentiviral vector coding for human WASP* under the control of a 1.6 kb reconstituted WAS gene promoter (LV-w1.6W) (3). The use of this endogenous promoter ensures that the transgene is expressed in a physiological manner (4), restoring WASP expression and function in human and murine WAS cells (3, 30–34). Its moderate enhancer activity combined with the SIN LTR design reduces the risk of insertional mutagenesis (35), as shown by in vitro transformation assays (36) and preclinical in vivo studies in WASP-deficient mice (34, 37). These data provided the rationale for a phase I/II clinical trial in which LV-w1.6W was used as a gene therapy vector for treatment of patients with WAS.

*WASP, a protein that regulates the cytoskeleton and mutated in the syndrome

An open-access paper published earlier this year in the journal Molecular Therapy (2) describes the role of studies undertaken in immunodeficient mice to develop and evaluate the lentiviral vector to treat Wiskott-Aldrich Syndrome in more detail.

In the Science paper (3) reporting the results of the trial of gene therapy in 3 boys with metachromatic leukodystrophy, the Telethon team highlight the key contribution of studies in mouse models of metachromatic leukodystrophy (MLD) in evaluating the ability of hematopoietic stem cells (HSCs) transformd using the lentiviral vector containing the functional arylsulfatase A  gene – deficient in MLD – to treat the disease:

In a mouse model of MLD, we have demonstrated that disease manifestations can be prevented and corrected by lentiviral vector (LV)–based HSC-GT but not by HSCT (8, 9, 16). This is consistent with the observation that HSCT fails to provide consistent benefits in MLD patients (3, 5–7). LV–based HSC-GT induced extensive and supra-physiological expression of the functional ARSA gene throughout the HSC progeny, which in turn mediated widespread cross-correction of CNS and PNS resident cells (8, 9).

This was only the last in a long series of animal studies that led to the clinical trial, an open-access review of progress being made in the development of gene therapy for a range of leukodystrophies published by Dr Biffi in 2011 highlights not only this important preclinical work, but also the basic and translational studies undertaken using a variety of different vector types in mice and monkeys that provided the data that allowed scientists to develop an effective therapy.

At a time when science and medicine in Italy is under attack from charlatans who are promoting dubious stem cell therapies, and scientific activists are campaigning against laws that threaten the very future of medical research in Italy, this weeks good news from the San Raffaele Telethon Institute for Gene Therapy is a reminder that there are many excellent scientists in Italy who are conducting medical research at the highest level, and that their work depends on animal research. We hope that this breakthrough – and there can be no doubt that this is a breakthrough – heralds a better future for science in Italy.

Speaking of Research

1) Aiuti A. et al. “Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome” Science. Published online 11 July 2013, DOI: 10.1126/science.1233151

2) Scaramuzza S. et al. “Preclinical safety and efficacy of human CD34(+) cells transduced with lentiviral vector for the treatment of Wiskott-Aldrich syndrome.” Mol Ther. 2013 Jan;21(1):175-84. doi: 10.1038/mt.2012.23.

3) Biffi A. et al. “Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy” Science. Published online 11 July 2013, DOI: 10.1126/science.1233158

4) Biffi A, Aubourg P, Cartier N. “Gene therapy for leukodystrophies.” Hum Mol Genet. 2011 Apr 15;20(R1):R42-53. doi: 10.1093/hmg/ddr142.