Gene therapy — delivering genetic material to treat disease — has survived multiple near-death experiences (patient deaths, leukemia induction in early trials) to reach genuine clinical maturity. The approvals of Luxturna, Zolgensma, hemophilia gene therapies, and now CRISPR-based Casgevy represent a new era.
## AAV Vector Gene Therapies
Adeno-associated virus (AAV) has become the dominant delivery vector for gene therapy. Different AAV serotypes preferentially infect different tissues: AAV9 crosses the blood-brain barrier (neurological diseases); AAV-rh10 targets liver; AAVAnc80 targets the cochlea. AAV rarely integrates into the host genome, reducing oncogenic risk compared to earlier retroviruses.
**Approved milestones**:
– **Luxturna (2017)**: the first true in vivo AAV gene therapy, treating RPE65-mutation retinal dystrophy (Leber congenital amaurosis) with a single subretinal injection. Partial vision restoration; list price approximately $850,000.
– **Zolgensma (2019)**: treats spinal muscular atrophy type 1 (SMA1) — the most common genetic cause of infant death — with a single IV infusion delivering the SMN1 gene. Children who previously could not survive are now developing normally. List price $2.1 million — then the world’s most expensive drug.
– **Hemophilia A and B**: multiple AAV therapies approved 2022–2023 deliver clotting factor genes to the liver, providing multi-year clotting function from a single infusion, eliminating the need for frequent factor replacement.
**Limitations**: AAV cargo capacity is approximately 4.7 kb, excluding large genes; patients may develop neutralizing antibodies (especially with prior natural AAV exposure), limiting re-dosing; delivery efficiency varies by tissue and individual.
## RNA Therapeutics: ASO and siRNA
Nucleic acid therapies modulate or silence specific RNAs without permanently altering DNA.
**Antisense oligonucleotides (ASOs)**: bind target mRNA to induce degradation or alter splicing. Spinraza (nusinersen) for SMA modifies SMN2 splicing to restore protein function through intrathecal injection three times yearly.
**siRNA**: double-stranded RNA triggering RNA interference-mediated gene silencing. Alnylam’s inclisiran silences PCSK9 mRNA to lower LDL cholesterol with just two annual injections — a significant advance in lipid management since statins. siRNA therapies have expanded across transthyretin amyloidosis, hyperlipidemia, and acute hepatic porphyria.
## In Vivo CRISPR
See [CRISPR Gene Editing](https://sunqi.org/crispr-gene-editing-advances-en/) for the Casgevy approval and Intellia’s Phase II in vivo liver editing data — the current clinical frontier.
## The Pricing Problem
Approved gene therapies are typically priced between $1 million and $3 million. Outcomes-based payment models (partial refunds if efficacy benchmarks are missed) are being explored by some payers. Balancing genuine innovation value with accessibility is the central commercial challenge facing the gene therapy industry.
For related reading, see [Synthetic Biology](https://sunqi.org/synthetic-biology-applications-en/), [CRISPR Advances](https://sunqi.org/crispr-gene-editing-advances-en/), and the review at [Nature Medicine](https://www.nature.com/articles/s41591-021-01501-8).
