Month: January 2015
Suicide Gene Therapy: The Genetic “Kill Switch”
What it is?
Suicide gene therapy is based on the introduction of a viral or a bacterial gene into tumor cells, which allows the conversion of a non-toxic compound into a lethal drug.
Basically suicide gene therapy also known as Gene Directed Enzyme/Prodrug therapy (GDEPT) or as Gene Prodrug Activation Therapy (GPAT) uses viral vectors to deliver suicide genes into tumor cells which possess the enzyme that converts prodrug to active metabolites, it increases the toxicity level several fold inside the tumor whereas the vast majority of the host cells are unaffected. Thus it accomplishes the same end goal of chemotherapy treatments, but by different means. While chemotherapy targets all of the body’s rapidly dividing cells with the intention of killing cancer cells, suicide gene therapy delivers a cancer-killing drug solely to tumors. This bypasses chemotherapy side effects like hair loss and nausea, which are caused by collateral damage to non-cancerous cells.
How it works?
There are several suicide gene therapies. Among them Herpes Simplex Virus thymidine kinase (HSV-tk) and Cytodine Deaminase (CD) are important. The Herpes Simplex Virus deposits a gene into the cancer cells that causes them to produce a special enzyme. Once the virus triggers production of the enzyme, doctors initiate step two by injecting the patient with a unique type of chemotherapy drug called a prodrug. Suicide gene therapy typically uses ganciclovir (GCV) and its nucleoside analogs (acyclovir etc). When administered, GCV and other prodrugs are nontoxic, and thus cause no harm to healthy cells.
But when GCV comes in contact with the special enzyme, the prodrug turns highly toxic. This starts a natural biological process called programmed cell death, which causes cells to commit suicide. Because HSV-tk and CD are not present in any of the body’s healthy cells, the prodrug only destroys cancer cells that were genetically altered by the virus.
Although only a limited number of tumor cells will take in HSV-tk or CD from the virus, the activated prodrug is passed on to neighboring cells through what doctors call the bystander effect. Further, cells that destroy themselves as a response to treatment attract immune cells that clear the tumor site of dead and dying cancer cells.
Limitations of (HSV-tk)-GCV system
This HSV-tk system suffers from limitations which include (i) the potential for production of inactive catalytic molecules due to the utilization of alternative splicing sites, (ii) the potential immunogenicity of the viral enzyme, (iii) the potential need to administer GCV to control cytomegalovirus infections (a complication often encountered in allo-HSCT) and thus cause unintended elimination of HSV/Tk-engineered cells, and (iv) the requirement for active cell division in order to mediate cell death, which takes time and renders the system less effective for use in post mitotic cells. Moreover, major improvements are needed in vector design to enhance targeting and delivery of suicide genes.
Live and Let Die: A New Suicide Gene Therapy
Despite of the limitations associated with HSV/tk-GCV system suicide gene therapy holds enormous potential in the eye of the researchers which is evident from the research done on combining suicide gene therapy with other treatments, improving the bystander effect and finding the optimal method for delivering GCV and the HSV-tk gene. One such example is iCasp9 (a late executor of the intrinsic pathway of apoptosis, leading to DNA fragmentation and rapid cell death) which represents more than a simple upgrade of the HSV/Tk-GCV system as it is not dependent on DNA synthesis as is HSV/Tk-GCV, allowing application in non-replicating cells. It involves dimerization of the subunits which is induced by addition of a biologically inert small molecule (AP1903) that has been shown in clinical studies to be well tolerated. Dimerization of iCasp9 activates one of the last steps in the apoptotic cascade, resulting in rapid cell death—as soon as 30 minutes after administration of the activator.
The field of suicide gene therapy is rapidly maturing and will no doubt be part of the future of cancer therapeutics. In addition, combination of Gene & Cell therapy approaches like “chimeric antigen receptors” or CARs for short also hold great promise for increasing the effectiveness of current chemotherapeutic treatment regimens.
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Only a hundred and fifty years have passed since Gregor Mendel’s discovery of simple Mendelian inheritance. In a remarkably short amount of time humans have achieved such impressive feats as sequencing the entire human genome and gaining understanding of the causes of most genetic disease. Now that researchers have all this information at hand, the focus has shifted to the design of reagents that can target specific genomic sequences. The rapid advancement of genome-editing techniques holds much promise for the field of human gene therapy. From bacteria to model organisms and human cells, genome editing tools such as zinc-finger nucleases (ZNFs), TALENs, and CRISPR/Cas9 have been successfully used to manipulate the respective genomes with unprecedented precision. With regard to human gene therapy, it is of great interest to test the feasibility of genome engineering because of their ease of customization and high-efficient site-specific cleavages that could potentially be used to treat a variety of human genetic disorders such as hemoglobinopathies, primary immunodeficiencies, and cancer.
Unraveling the potential of CRISPR-Cas9 for gene therapy
The molecular machinery from the prokaryotic clustered regularly interspaced short palindromic repeats (CRISPR)-Cas immune system has broadly been repurposed for genome editing in eukaryotes. In particular, the sequence-specific Cas9 endonuclease can be flexibly harnessed for the genesis of precise double-stranded DNA breaks, using single guide RNAs that are readily programmable. The endogenous DNA repair machinery subsequently generates genome modifications, either by random insertion or deletions using non-homologous end joining (NHEJ), or designed integration of mutations or genetic material using homology-directed repair (HDR) templates. This technology has opened new avenues for the investigation of genetic diseases in general, and for gene therapy applications in particular.
Patent Litigation over control of the revolutionary CRISPR-Cas9 tech
Despite the predicted utility of a successful gene editing technique, many current methods like Zinc Fingers Nucleases and TALENs have confounding issues like low efficiency, time-consuming procedures, and lack of specificity for both model organisms and humans. In the past several years, a new gene editing system viz, CRISPR-Cas9 derived from bacteria, has arisen as a frontrunner for efficient and successful gene editing.
Research in the area of CRISPR/Cas9 is gaining speed and this system could very well be the solution to many medical issues we face today. For evidence of CRISPR/Cas9’s promise, look no further than its attendant battle over intellectual property. Novartis and Atlas Venture joined together to form Editas Medicine, but a breakup of co-founders led Berkeley’s Jennifer Doudna to take her IP to the competing Intellia Therapeutics, while Swiss rival CRISPR Therapeutics has conflicting claims of its own backed by Versant. And now a team at Johns Hopkins has done some experiments to demonstrate its promise in engineering human stem cell therapies.
This proves that gene editing has staggering potential and that it can be developed as a naturalistic method of correcting defective genes by getting at the underlying causes of a broad range of diseases.
Gene Therapy’s fruition?
The world of gene therapy in which single-dose treatments correct debilitating defects enjoyed something of a renaissance in 2014. Strong clinical results from leaders in the once-maligned field spurred renewed optimism, helping a new generation of startups secure millions in venture financing to develop their next-generation approaches to the field. And that led to something of a trickle-up phenomenon in the industry, as the innovations of biotechs and academics convinced the world’s biggest players to give this field a second look. Now Bayer, Pfizer, Biogen Idec and Astellas are among the many companies toiling in gene therapy, joining high-profile biotechs like bluebird bio and uniQure.
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