Biologics (Cell Therapies. gene Therapy)

Question 1

What are biological therapies?

Answer 1

• Peptides / recombinant therapies
• Gene therapy
• Cell therapy
• Monoclonal antibodies

Question 2

What is gene therapy?

Answer 2

The transfer of genetic sequences that alter the DNA of a cell for therapeutic purposes

Delivery of genetic sequences that alter the instruction set of a cell for therapeutic purposes

Question 3

What are the genetic sequences used in gene therapy?

Answer 3

• Synthetic copies of genes that encode a specific protein

- Short genetic sequences that knockdown the expression of a specific gene

Question 4

Whats a variation of gene therapy?

Answer 4

Somatic cell gene therapy

Question 5

What is somatic cell gene therapy?

Answer 5

Therapy is restricted to the patient and genetic material is not passed onto their offspring

Question 6

What would the ideal gene therapy approach be?

Answer 6

• Be highly specific leading to reduced side effects

- Produce a long term therapeutic effect following a single application

Question 7

What would ideal gene therapy involve?

Answer 7

Aim: To deliver the therapeutic gene to the organ/cell of interest

Problem: Mammalian cells are very efficient at getting rid of foreign DNA

Solution: Therapeutic genes are delivered using gene delivery vehicles

Question 8

What are the gene delivery vehicles?

Answer 8

• Non-viral vectors : PLasmids, siRNA, lipsomes

- Viral vectors: Genetically modified viruses

Question 9

How are viruses used as vectors?

Answer 9

• Exploit the natural life cycle of a virus
• Viruses bind to membrane bound receptors and have evolved efficient ways to gain access to the nuclear transcriptional machinery
• Remove the virus replication genetic material, left with shell, replace with therapeutic transgene
• most viral vectors nowadays are safe

Question 10

How do viral vectors work?

Answer 10

-Penetrate a cell, use its nuclear machinery and produce therapeutic proteins(no viral genes replicated)

Question 11

Whats the difference between ex-vivo and in-vivo gene therapy?

Answer 11

Ex-vivo = Genetic modification performed on cells in a dish before transplantation in the patient

In-vivo = Genetic modification performed directly in the patient

Question 12

What does the success of gene therapy depend on?

Answer 12

Success of gene therapy depends on the efficiency of gene transfer

Question 13

Whats the example for gene therapy?

Answer 13

Parkinsons disease

Question 14

What does PD primarily affect?

Answer 14

Loss of dopamine cells in SNpc

Question 15

Whats the stage one strategy for pd?

Answer 15

Dopamine replacement

Question 16

How does dopamine replacement work?

Answer 16

Aim: Increase dopamine synthesis locally in the striatum

How: Transfer genes involved in dopamine synthesis to the neurons in the striatum

Problems: Does not prevent disease progression; amount of dopamine produced is hard to control

Question 17

What is the second strategy for PD?

Answer 17

Neuroprotection

Question 18

How does neuroprotection work for PD?

Answer 18

Aim: Boost production of growth factors involved that promote dopamine cell survival and axonal regeneration i.e glial cell derived neutrotrophic factor (GDNF) and Neurturin

How: Introduce GDNF or Neurturin genes into the brain

Question 19

What is cell therapies?

Answer 19

Therapies involving the injection of living cells into a patient i.e bone marrow transplants

Question 20

What are the types of cell therapies?

Answer 20

Autologous : Cells removed from patient, modified and returned

Allogenic : Cell donor is different person

Syngeneic : Cell donor is genetically identicle (twins)

Question 21

What sorts of cells are used in cell therapy?

Answer 21

Cells can vary:

• Stem cells (cultivated into other cells)
  
  • Blastocyte
  • heDSC
  • adult CNS
  • Fetal CNS
  • Bone marrow
  • Fibroblast

Question 22

How do cell therapies work?

Answer 22

• Replace damaged tissue

- Release therapeutic proteins

Question 23

How does the replaced damaged tissues cell therapy work?

Answer 23

-Stem cells or progenitor cells are differentiated into a specific cell type in the lab. Cells are grafted into site of injury

Question 24

How does the release therapeutic proteins cell therapy work?

Answer 24

• Transport cells that have the capacity to release soluble factors i.e cytokines, chemokines, growth factors
  e. g insulin

Question 25

What are antibodies?

Answer 25

Antibodies (immunoglobulins) are proteins that fucntion to identify and neutralize pathogens such as viruses or bacteria

Antibodies recognize and bind to specific antigens

Question 26

What does monoclonal antibodies for human therapies involve?

Answer 26

• Specific for one antigen
• Typically iGg subtype
• Have been humanized or are chimeric antibodies
• Currently, commerical antibody therapies are mainly for cancer and immune disorders

Question 27

What are the modes of action for many cancer immunotherapies?

Answer 27

• Antibody binds to a soluble ligand involved in cancer growth
• Antibody binds to a cell surface receptor on a tumor cell
• Antibody binds to tumor antigen induces human immune effector responses

Question 28

What happens when Antibody binds to a soluble ligand involved in cancer growth?

Answer 28

• Interferes with its activity and interaction with binding partners
  i. e avastin (Bevacizumab) used for treating colorectal cancer, binds to the ligand VEGF-A

Question 29

What happens when Antibody binds to a cell surface receptor on a tumor cell?

Answer 29

• Blocks its interaction with a ligand
• Interferes with signalling pathways important in maintaining tumor growth
• triggers receptor internalisation or apoptosis of tumor cells

i.e trastuzumab (herceptin) used for treating metastatic breast cancer targets HER2 receptor