Brief discussion on gene therapy with recent innovations and recently approved medicines and their mechanisms.

1. INNOVATIONS:
ARRIVAL OF GENE THERAPY
L. M. COLLEGE OF PHARMACY
DEPARTMENT OF PHARMACEUTICS AND TECHNOLOGY
PREPARED BY:
DR. YAMINI D. SHAH,
MR. VATSAL SHAH

2. • Gene therapy has emerged as a new concept of therapeutic strategies to treat diseases which do
not respond to the conventional therapies.
• The principle of gene therapy is to introduce genetic materials into patient cells to produce
therapeutic proteins in these celss.
• Gene therapy is now at the stage where a number of clinical trials have been carried out to
patients with gene deficiency disease or cancer.
• Genetic materials for gene therapy are generally composed of gene expression system and gene
delivery system.
• For the clinical application of gene therapy in a way which conventional drugs are used,
researchers have been focused on the design of gene delivery system which can offer high
transfection efficiency with minimal toxicity.
Introduction to Gene therapy

3. Introduction to Gene therapy
• Gene therapy means a type of DNA based medicine that inserts a healthy gene into cells to
replace a mutated, disease causing variant.
• This idea was first published in 1972. Then the period between 2020 to 1972 saw disputes
in hypothesis, results, failures in the treatments and some deaths in experimental trials.
• China was the first country to approve a gene therapy drug for one type of skin cancer in
2005.
• Apart from China, no other country was ready to accept the benefits of such drugs.
• Then in 2017, US approved one of these medicines since then, the pace of approvals has
increased quickly. At least nine gene therapies have been approved for certain kinds of
cancers, some viral infections and a few inherited disorders.

4. In general, how these medicines work?
• A related drug type interferes with faulty genes by using stretches of
DNA or RNA to obstruct their workings. Therefore one may admit that
nearly after five decades, the concept of genetic medicine becomes a
reality.
Mechanisms of
gene therapy
Gene Insertion
Gene
Interference

5. Gene Insertion
• These treatments use a harmless virus to carry a good gene into cells,
where the virus inserts it into the existing genome, cancelling the
effects of harmful mutations in another gene.

6. Gene Interference
• This approach uses a synthetic strand of RNA or DNA (called an
oligonucleotide) that, when introduced into a patient’s cell, cell attach
to a specific gene or its messenger molecules, effectively inactivating
them, some treatments use an antisense method, named for one DNA
strand, and others rely on small interfering RNA strands, which stop
instruction molecules that go from the gene to the cell’s protein
factories.

8. DRUGS APPROVED
FOR
GENE THERAPY

9. Sr. No. Drugs
1 Gendicine
2 Glybera
3 Imlygic
4 Kymriah
5 Luxturna
6 Strimvelis
7 Yescarta
8 Zolgensma
9 Zynteglo
10 Spinraza
11 Macugen
12 Kynamro
13 Exondys 51
14 Defitelio

10. Gendicine
• Country Approved - First drug approved by China – 2003
• Use -
For the treatment of head and neck squamous cell carcinoma, a type of
skin cancer.

11. Head and neck squamous cell carcinoma

12. • Mode of action –
A virus engineered to carry a gene which replicates, transcribes and
carry the codes for expressing and translating into protein for
mutation.
This protein fights against tumor, thereby virus introduces the gene
into tumor cells, causing them to increase the expression of tumor-
suppressing genes and immune response factors.
However USFDA still needs to approve this medicine.

13. Glybera
• Country approved - First gene therapy approved in European Union
• Use -
For Treatment of Lipoprotein lipase deficiency (LPLD), a rare
inherited disorder that can cause severe pancreatitis.

14. Pancreatitis

15. • Mode of action -
The drug would insert the gene for lipoprotein lipase into muscle
cells. But because LPLD occurs in so few patients, the drug was
unprofitable.
By 2017 its manufacturer declined to renew its marketing
authorization. It is no longer on the market.

16. Imlygic
• Country approved - China, US, EU
• Use -
Melanoma (to treat skin lesions following initial surgery)

18. • Mode of action -
Viral vector is inserted directly into the tumor cells wherein due to
replication of gene a protein is produced which stimulates an immune
response to kill cancer cells.

19. Kymriah
• Country approved - USFDA - 2017, EU - 2018
• Use -
B – cell lymphoblastic leukemia ( A type of cancer that affects white
blood cells in children and young adults. )

20. B – cell lymphoblastic leukemia

21. • Mode of action -
Works by introducing a new gene into a patient’s own T-cells that
enables them to find and kill cancer cells.

22. Luxturna
• Country approved - USFDA – 2017, EU – 2018
• Use -
To treat a rare form of inherited blindness known as “Biallelic RPE 65
– mutation associated retinal dystrophy”.
This disease affects between 1000-2000 patients in the US, who have
a mutation in both copies of a particular gene-RPE 65.

23. Retinal Dystrophy

24. • Mode of action -
The drug delivers a normal copy of RPE 65 to patient’s retinal cells,
allowing them to make a protein necessary for converting light to
electrical signals and restoring their vision.

25. Strimvelis
• Country approved - EU – 2016
• Use -
About 15 patients in Europe are diagnosed with a rare inherited
condition called adenosine deaminase deficiency (ADA-SCID).
The patient’s body can not make this enzyme vital for healthy white
cells.

26. Adenosine deaminase deficiency (ADA-SCID)

27. • Mode of action -
Drug works by introducing the gene responsible for producing ADA
into stem cells taken from patient’s own marrow.
Then cells are reintroduced into patient’s blood stream, where they are
transported to the bone marrow begin production of normal white
cells-ADA.

28. Yescarta
• Country approved - FDA – 2017, EU – 2018, China – in clinical trials
• Use -
Large B cell lymphoma that affects white cells called lymphocytes.

29. Large B cell lymphoma

30. • Mode of action -
Treatment known as part of CAR-T cell therapy.
The virus inserts a gene which codes for CAR-proteins known as
chimeric antigen receptors into a patient’s T-cells.
These cells introduced into the patient’s body where CARs allow T-
cells to attach to and kill cancer cells in the blood stream.

31. Zolgensma
• Country approved - USFDA – May 2019
• Use -
For children younger than 2 years with spinal muscular atrophy, a
neuromuscular disorder that affects about 1 in 10000 people
worldwide.

32. Spinal muscular atrophy

33. • Mode of action -
• Zolgensma binds to RNA from a “backup” gene called SMN2,
coverting that RNA into instructions for making fully functional SMN
proteins.

34. Zynteglo
• Country approved - EU – 2019
• Use -
• Treats a blood disorder called beta-thalassemia that reduces a patient’s
ability to produce haemoglobin, the protein in red blood cells that
contains iron, leading to life-threatening anemia.

36. • Mode of action -
The therapy has been approved for individual 12 years and older who
require regular blood transfusions.
It employs a virus to introduce healthy copies of the gene for making
Hb into stem cells taken from the patient.
The cells are then reintroduced into the bloodstream and transported
into the bloodstream and transported to the bone marrow where they
begin producing healthy lymphocytes that can manufacture Hb.

37. Spinraza
• Country approved - FDA - 2016
• Use -
• First gene therapy for spinal muscular atrophy.
• Inherited disorder caused due to low levels of SMN, a key protein for
maintenance of motor neurons.

38. Spinal muscular atrophy

39. • Mode of action -
Spinraza binds to RNA from a “backup” gene called SMN2, coverting
that RNA into instructions for making fully functional SMN proteins.

40. Macugen
• Country approved - US
• Use -
Age related macular degradation
A leading cause of vision loss in people age 60 and older
Caused due to deterioration of the center of the retina due to leaking
blood vessels.

42. • Mode of action -
This drug inhibits these blood vessels from growing under the retina,
thereby treating the disorder.

43. Kynamro
• Country approved - USFDA – 2013
• Use -
Hyper-cholesterolemia or High cholesterol level.

44. Hyper-cholesterolemia

45. • Mode of action -
This drug inhibits or shuts down production of a protein that helps to
produce LDL through subcutaneous injection thus lowering LDL
levels in patients who have dangerously high cholesterol.

46. Exondys 51
• Country approved - USFDA – 2016 (controversial drug)
• Use -
Duchenne muscular dystrophy.
Caused due to mutations in the RNA.
This disease occurs in about 13 percent of the Duchenne population.

47. Duchenne muscular dystrophy

48. • Mode of action -
This drug treats by correcting RNA by inhibiting the coding for such
proteins that helps to connect muscle fibre’s cyto-skeletons to a
surrounding matrix.

49. Defitelio
• Country approved - With limitations approval by USFDA and EU in 2017
• Use -
Severe cause of veno-occlusive disease – a disorder in which small veins of
the liver become obstructed in patients who have received a bone marrow
transplant.

50. Hepatic veno-occlusive disease

51. • Mode of action -
Drug contains a mixture of single strand oligonucleotides obtained
from the intestinal mucosa of pigs.

52. CURRENT SCENARIO
• Currently viral delivery systems generally provide higher transfection
efficiency compared with non-viral delivery system where as non-viral
delivery systems are less toxic, less immunogenic and manufacturable
in large scale compared with viral systems.
• Recently, novel strategies towards the design of new non-viral delivery
system, combination of viral and non-viral delivery system and
targeted delivery system have been extensively studied.

53. THANK YOU!!!