Gene therapy involves inserting therapeutic genes into a patient's cells to treat disease. It began in clinical trials in 1990 and has had some success treating cystic fibrosis. There are two main types: somatic gene therapy treats cells in the body while germline gene therapy treats sperm, egg, or embryo cells and can be passed down. Current applications include treating genetic diseases, cancer, and blocking viruses like HIV. Clinical trials often involve modifying blood cells or stem cells from leukemia/lymphoma patients before transplant. While gene therapy shows promise, there are also risks like unwanted gene insertion and ethical concerns over cost, eligibility, and altering the germline.

1. GENE THERAPY
Correcting defective genes

2. WHAT IS GENE THERAPY ?
• Gene therapy is the delivery of therapeutic gene into a patient's cells to
treat disease.
• Gene Therapy approaches that seek to insert genes into a patients’ own
cells to control or kill HIV are in clinical trials now.

3. DEFINITION & HISTORY
• Normal gene inserted into the genome to replace non-functional gene
• Trials began in 1990
• Cystic fibrosis gene moderately successful

4. TYPES OF GENE THERAPY
• gene therapy may be classified into two types
• somatic
• germline

5. OBJECTIVES
 Learn about how therapies that insert genes and use cells is on the brink
of transforming medicine and curing disease.
 Learn how Gene/Cell therapies fit into HIV cure efforts
 Learn the targets, techniques, and cell types used in HIV Gene/Cell
Therapy

6. VECTORS
• Viruses eg retro viruses, adenoviruses (commonly used)
• Direct introduction (“golden bullets”)
• Liposomes
• Endocytosis of DNA bound to cell surface receptors (low efficiency)
• Artificial chromosome (under development))

7. APPLICATIONS
• Curing genetic diseases
• Correcting cancer genes
• Inducing cancerous cells to make toxins so they kill themselves
• Blocking viral genes (e.g. HIV)
• Creating stem cells from somatic cells

8. DIFFERENT ROUTES OF GENE THERAPY
• Ex vivo gene therapy -
• Usually with blood cells (lymphocytes or blood stem cells) for diseases
affecting the hematopoietic system
• In vivo gene therapy -
• Oncolytic adenoviruses for the treatment of cancer
• Adeno-associated vectors for the treatment of Duchenne muscular
dystrophy or hemophilia
• Non-viral for cancer

9. CLINICAL TRIALS—BLOOD CANCER
PATIENTS
 Many trials recruit lymphoma or leukemia patients who need a
transplant
 Undergo conditioning to eliminate current immune system to create
space for a new system
• Their HSCs are gene modified to resist HIV, and are then transplanted
back into the participant in a mix of modified and unmodified cells.

10. GENE THERAPY IN BLOOD
CELLS
s

11. GENE THERAPY CLINICAL TRIAL
CONCERNS
 Gene therapy trials involve different gene editing/modifying
techniques.
 Precision is key, a serious concern is “off target” editing.
 If the genes other than those targeted are modified (off target editing),
the potential for serious adverse events exist, including cancer.

12. PROBLEMS
• Acute immune response to viral vectors
• Repeated treatment needed
Genes “lost” when the cell goes through mitosis
• Viral vectors could become pathogenic
• Genes spliced at random into the genome could upset other genes
• Multigene disorders too complex to treat

13. ETHICAL PROBLEMS
• Gene therapy for serious genetic diseases OK but for other health
problems?
• Somatic cell treatment stays with the individual, germ cell treatment
passes down the germ line (becomes immortal)
• Very costly. Who pays? Who is eligible?

14. TREATMENT INTERRUPTIONS
 Seen as essential to allow modified cells to engraft and increase as a
proportion of the cell population and to allow HIV to kill unprotected
cells, and thus select for modified cells.
 This process carries potential risks like treatment regimen resistance

15. INDUCED PLURIPOTENT STEM CELLS
(IPSC)
• Skin cells are converted back into embryo-like state (pluripotency )
• The pluripotent cells are modified to have a deletion of CCR5Δ32 mutation
• Modified cells differentiated and returned

16. GENE THERAPY APPROACHES
 The “kill” in “Kick and Kill”, (Lam, Baylor)
 T cells are taken from the peripheral blood of patients suppressed on
antiretroviral therapy.
 The cells are presented with multiple HIV antigens and then expanded.
 Cells are functional and have broadly specific and potent HIV infected
cell killing ability and the ability to suppress HIV replication.

17. THE FUTURE
• Gene therapy on sex cells of carriers
• Gene therapy on fertilised egg cells

18. ADVANTAGES OF GENE THERAPY
• Gene silencing is a concept that in itself is self-efficient for management
of many diseases.
• Gene therapy has the potential to eliminate and prevent hereditary
diseases, such as cystic fibrosis, and is a possible cure for heart
disease,,AIDS and cancer.
• Gives an advantage to a person born with genetic disorder to live life in
a normal way by replacing non-functional gene with a functional one.

19. DISADVANTAGES OF GENE THERAPY
1. Irregular immune responses.
2. Viral vectors may introduce toxicity, as well as immune and inflammatory responses.
3. Multi-gene disorders such as heart disease, high blood pressure, Alzheimer’s disease, arthritis,
and diabetes cannot be treated through this therapy as conditions or disorders that arise only
from mutations in a single gene are the best candidates for gene therapy.
4. Religious concerns.
5. Chances of inducing iatrogenic (physician induced) tumours in human beings

20. CONCLUSIONS
 Regenerative Medicine/Cell-Gene Therapy is a rapidly maturing field
offering potential for cures and therapies in several diseases and
conditions
 Clinical trials in HIV are underway or planned
 A functional cure may result, but clinical benefit such as increased T
cells for immunological non-responders would also help some patients
greatly. And cell/gene therapy could provide the “kill” in “kick and kill”.
It doesn’t have to lead to a cure by itself.

21. PRESENTED BY : V. VIGNESH