How does the European Medicines Agency (EMA) define gene therapy medicinal products (GTMPs)?
A. EMA defines "gene therapy medicinal products (GTMPs) generally consist of a vector or delivery formulation/system containing a genetic construct engineered to express a specific transgene ('therapeutic sequence') for the regulation, repair, replacement, addition or deletion of a genetic sequence. The active substance is the nucleic acid sequence(s), or genetically modified microorganism(s), virus(es) or cells.
B. EMA defines that a gene therapy medicinal product is a biological medicinal product.
C. EMA defines that a gene therapy medicinal product fulfills the following two characteristics: (a) it contains an active substance which contains or consists of a recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence; (b) its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence.
D. Gene therapy medicinal products shall not include vaccines against infectious diseases.
Which of the following statements about gene editing by CRISPR/Cas9 are correct?
A. On Jan 21, 2018, The Wall Street Journal reported that 86 people in China have had their genes edited using CRISPR/Cas9.
B. In April 2015, Chinese scientists reported results of an attempt to alter the DNA of non-viable human embryos using CRISPR/Cas9 to correct a mutation that causes β-thalassemia. The study had previously been rejected by both Nature and Science in part because of ethical concerns. The experiments resulted in changing only some genes, and had off-target effects on other genes. The researchers stated that CRISPR/Cas9 is not ready for clinical application in reproductive medicine.
C. In April 2016, Chinese scientists were reported to have made a second unsuccessful attempt to alter the DNA of non-viable human embryos using CRISPR/Cas9 - this time to alter the CCR5 gene to make the embryo HIV resistant.
D. Heritable modifications could have unintended and far-reaching consequences for human evolution, genetically (e.g. gene/environment interactions) and culturally (e.g. Social Darwinism). Altering of gametocytes and embryos to generate inheritable changes in humans was defined to be irresponsible.
Which of the following statements about CRISPR/Cas9 (clustered, regularly interspaced short palindromic repeat/CRISPR-associated protein 9) are correct?
A. The genes encoding the Cas9 protein & single guide RNA (sgRNA) are introduced into a cell where a targeted genomic change is planned.
B. The sgRNA has a region complementary to the chosen genomic target sequence; this region can be engineered to include any desired sequence. A complex consisting of the CRISPR sgRNA & the Cas9 protein forms within the cell & binds to the chosen target site in the DNA.
C. 2 nuclease active sites in the Cas9 protein separately cleave each DNA strand in the target, producing a double-strand break. The double-strand break is usually repaired by nonhomologous end joining, which generally deletes or alters the nucleotides at the site where joining occurs.
D. In the presence of a recombination donor DNA fragment, identical to the target sequence but incorporating the desired sequence change, homologous DNA recombination will sometimes change the sequence at the site of the break to match that of the donor DNA.
What are the major hurdles for the success of gene therapy?
A. Short-lived nature – Before gene therapy can become a permanent cure for a condition, the therapeutic DNA introduced into target cells must remain functional & the cells containing the therapeutic DNA must be stable. Problems with integrating therapeutic DNA into the genome & the rapidly dividing nature of many cells prevent it from achieving long-term benefits. Patients require multiple treatments.
B. Immune response – Any time a foreign object is introduced into human tissues, the immune system is stimulated to attack the invader. Stimulating the immune system in a way that reduces gene therapy effectiveness is possible.
C. Multigene disorders – Some commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer's disease, arthritis, & diabetes, are affected by variations in multiple genes, which complicate gene therapy.
D. Some therapies may breach the Weismann barrier (between soma and germ-line) protecting the testes, potentially modifying the germline, falling afoul of regulations in countries that prohibit the latter practice.
The major risks for gene therapy include:
A. Gene therapy can trigger the immune response in the patient, that could be harmful to them. Retroviruses has raised skepticism about their safety. Deactivated viruses are really deactivated?
B. Viral vectors may cause toxicity, infection, inflammation, etc.
C. Gene therapy may cause off-target effects— there is a risk that the new gene will insert itself into the path of another gene, disrupting its activity, or cause insertional mutagenesis.
D. Gene therapy may cause chronic granulomatous disease and cancer.
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