Describe gene therapy approaches
WHY does gene therapy exist?
WHAT problem does it solve? Many diseases (cystic fibrosis, SCID, haemophilia, some cancers) are caused by a faulty or missing gene. Conventional drugs only manage the downstream consequences. Gene therapy attacks the cause: the DNA itself.
The two big axes for classifying approaches
Every gene therapy is described by two independent questions:
Any real therapy is a combination, e.g. "somatic, ex vivo" (like CAR-T / SCID treatment).
The three functional strategies (WHAT you do to the gene)
HOW is the gene delivered? (Vectors)
| Vector | Integrates into genome? | Consequence |
|---|---|---|
| Retrovirus | Yes (dividing cells) | Long-lasting, but insertion risk |
| Lentivirus | Yes (also non-dividing) | Long-lasting |
| AAV | Mostly episomal | Safer, but diluted as cells divide |
| Liposome | No | Transient, safe |
Worked example 1 — SCID ("bubble boy" disease)
Disease: mutation in ADA gene → no adenosine deaminase → dead immune cells.
- Step 1: Extract patient's bone-marrow stem cells. Why? → ex vivo gives control & safety checks.
- Step 2: Use a retro/lentiviral vector to add a working ADA gene. Why viral? → high efficiency into stem cells.
- Step 3: Re-infuse cells. Why stem cells? → they self-renew, so the fix persists as they repopulate blood.
Classification: somatic + ex vivo + gene augmentation.
Worked example 2 — Cystic fibrosis (CFTR)
- Faulty CFTR chloride channel in lung epithelium.
- Deliver working CFTR gene via liposome aerosol / AAV inhaled directly to lungs. Why in vivo? → you can't remove lung lining cells.
- Classification: somatic + in vivo + gene augmentation. Challenge: lung cells turn over, so it must be repeated.
Worked example 3 — Huntington's disease
- Caused by a dominant toxic mutant huntingtin protein.
- You can't just add a good copy (bad copy still poisons). Why? → dominant. So use gene silencing (siRNA/CRISPR knockdown of the mutant allele).
- Classification: somatic + in vivo + gene silencing.
Recall Feynman: explain to a 12-year-old
Your body follows an instruction book (DNA). Sometimes a page has a typo that makes you sick. Gene therapy is like: (1) taping in a good copy of the page (add), (2) crossing out a bad page that gives wrong orders (silence), or (3) using tiny scissors to fix the exact typo (edit). To carry the new page in, we use a delivery van — sometimes a tamed virus (fast) or a tiny fat bubble (safe). If we fix cells that keep making copies of themselves, the fix lasts a long time.
Flashcards
Somatic gene therapy — inherited or not?
Germline gene therapy alters what, and why is it banned?
Difference between in vivo and ex vivo gene therapy?
Which strategy suits a recessive loss-of-function disease?
Which strategy suits a dominant toxic-protein disease?
What is gene editing (vs augmentation)?
Why use viral vectors despite risks?
Main risk of retroviral vectors?
Why does AAV therapy often need repeat dosing?
Why target stem cells in SCID therapy?
Why is cystic fibrosis treated in vivo?
Advantage and drawback of liposome (non-viral) vectors?
Connections
- CRISPR-Cas9 mechanism — the molecular tool for gene editing
- Viral vectors and vector design
- Recombinant DNA technology — how the working gene copy is made
- SCID and CAR-T cell therapy — ex vivo somatic examples
- Dominant vs recessive inheritance — decides augment vs silence
- RNA interference (siRNA/shRNA) — silencing mechanism
- Ethics of germline editing
Concept Map
Hinglish (regional understanding)
Intuition Hinglish mein samjho
Gene therapy ka core idea simple hai: bimari ki jad yaani DNA ko theek karo, sirf symptoms ka ilaj mat karo. Normal dawai to baar-baar leni padti hai, par agar gene hi sahi kar do to problem apne source par ruk jaati hai. Isko samajhne ke liye do sawaal poochho — (1) kaunse cells badal rahe ho, aur (2) kahan editing kar rahe ho.
Pehla axis: somatic (body cells, sirf patient tak, next generation ko nahi jaata) vs germline (gametes/embryo, bacchon ko inherit ho jaata — isliye humans mein ban hai). Doosra axis: in vivo (vector seedha patient ke body mein daala) vs ex vivo (cells nikalo, lab mein theek karo, check karke wapas daalo — jaise SCID treatment).
Teen strategies yaad rakho: Augment (working copy add karo — recessive/loss-of-function bimari ke liye, jaise CF, SCID), Silence (toxic gene ko band karo — dominant bimari, jaise Huntington's), aur Edit (CRISPR se exact mutation ko rewrite karo — sabse precise). Gene ko andar pahunchane ke liye vector chahiye: viral (fast par immune/insertion risk) ya non-viral liposome (safe par kam efficient).
Sabse important exam trick: augment sirf tab kaam karta hai jab bad gene silent ho (recessive). Dominant toxic protein ke liye add karna bekaar hai — silence ya edit karna padega. Aur permanence tabhi milti hai jab gene genome mein integrate ho ya stem cells target ho; warna (AAV/liposome, ya lung cells) dose repeat karni padti hai. Yeh do points 80/20 hain — inse zyada marks aate hain.