Washington D.C: A team of researchers at the University of Massachusetts Medical School, led by an Indian neuroscientist, has developed a non-invasive gene therapy to treat brain tumour. Currently, treatment for brain tumour or Gliobastoma (GBM) involves surgery, followed by radiation and chemotherapy with temozolomide.
Still, complete surgical removal of tumour is nearly impossible, as these cells are also radio and chemotherapy resistant. Thus, tumour recurs in a few months after surgery and finally causes death. Even with the best of treatment, only 3% patients survive up to five years.
One of the major difficulties to treat glioblastoma, is the tumour cells are highly migratory and they travel long distances within the brain as single cell infiltrates and invades within other tissues. These single cell infiltrations are difficult to detect in the MRI scan, and also almost indistinguishable from healthy tissues in the brain.
Thus, it is impossible to remove the tumour completely in a surgery. Since, the overall survival of a GBM patient post diagnosis is less than two years, medical scientists have been exploring therapeutic approaches to prevent recurrence of tumour.
According to a report appearing in the Indian Science Journal, a team of scientists led by Dwijit Guha Sarkar, of University of Massachusetts Medical School, researched the possibility of such an approach and found a systemic delivery approach of viral vector mediated gene therapy injection in the blood, with Interferon beta (IFNb) gene.
IFNb is a cytokine secreted from cells upon viral infection, and activates several genes downstream. It is a cytokine, which is a class of secreted proteins that play important immune functions in our body. IFNb is naturally secreted from our body cells as a part of immune protective mechanism when there is a viral infection.
It can modulate ~300 other gene expressions downstream, and can activate many biochemical pathways. Interestingly, other than its role as immune-modulator, it has several anti-tumour functions. It can inhibit cancer cell division, prevent new blood vessel formation (angiogenesis) in tumour, can also sensitize some chemo-resistant tumour cells to some chemotherapeutic drugs.
“In search for a new therapeutic approach, in this study we examined (in a mouse model) a method of gene therapy. We have implanted highly invasive and aggressive human glioblastoma tumour cells in the mouse brain. We allowed it to graft and grow. Then we treated these animals with our new gene therapy approach. We have used adeno-associated viral vector (AAV) mediated interferon-beta (IFNb) gene therapy,” Guha Sarkar told Indian Science Journal.
Gene therapy involves supplementing, silencing, correcting, or providing with genes having therapeutic benefit. Traditionally, gene therapy is a strategy, most commonly being tested for treatment of single gene disorders, where a single non-functioning or bad (mutated) gene is responsible for the disease. Gene therapy strategy usually supplements the body with a good version of the gene or silences a gene, producing toxic proteins.
More recently, a new approach of gene therapy is also attempting to correct the bad gene by editing the genome – the complete set of genetic material present in a cell of a host organism, instead of just supplementing or silencing. Scientists have tested different gene therapy approaches to treat cancers.
But, glioblastoma and many other cancers are often caused by abnormal functioning of multiple genes that involve a complex pathological mechanism, which is still to be completely understood. So, simply supplementing, silencing or editing one gene is not sufficient to treat these cancers.
Therefore, scientists needed to take different approaches. One of them is to deliver some genes to the cancer cells, where the genes express proteins that can directly or through activating a drug can kill the same cancer cells that are producing that protein. Those genes are called “suicidal genes” as they kill the same cells where they are produced.
If gene delivery can be done specifically and efficiently to the cancer cells, minimizing the suicidal gene transfer to the healthy normal cells, this approach could be promising. But often gene delivery to cancer cells is a very inefficient process and difficult to achieve specific targeting. Hence, only some cancer cells that receive the suicide genes die, but many cells escape the treatment, which causes recurrence of tumour.
“We found that this treatment was effective in a dose-responsive manner, and an optimum dose could completely eliminate the highly invasive tumour from mouse brain and provided long term survival benefit. At the end of the study, we analyzed the brain microscopically, using tissue and tumour staining, where we could not detect any remaining or recurring tumour in the treated animals,” added Guha Sarkar.
“We also found that this intravenous delivery approach (injecting in the blood) was far superior to local treatment approach for treating a condition with multiple distant tumours,” Guha Sarkar said. “The result of the current study is very exciting and demonstrates a promising new approach,” Sarkar added.
But, there are a few more challenges that have to be addressed before moving on to human trials. One of them is that, these mice used for human tumour grafting were for obvious reasons immune-compromised, so they don’t reject the human-origin cells.
But body’s immune system interacts with the tumour in a complex mechanism and plays important role in tumour prognosis. Moreover, IFNb as a molecule has immune-modulatory role when expressed in the species-matched host. Human IFNb over-expression in human body can potentially have detrimental side effects unless expressed in a regulated manner.
Hyper-activation of immune system by continuous expression of IFNb could also have possible toxic effects in the long term, unless the expression can be switched off, when it is not needed anymore. These issues have to be taken care of before this approach can be successfully replicated in human beings.
Guha Sarkar is an alumnus of the University of Calcutta and plans to take up post-doctoral research in Bose Institute, Kolkata, after his current research under the guidance of Miguel Sena-Esteves at University of Massachusetts Medical School....