Advances in Gene Therapy

Things are moving very fast in the area of gene therapy. Remember, while gene therapy that changes somatic cells is considered morally acceptable by the Vatican, any gene therapy that changes gametes is considered sinful by the Catholic Church because it corrects the defects for all subsequent generations and engineers a "better" human being (i.e., it is eugenics). 

1. Donum Vitae (1987): This document from the Congregation for the Doctrine of the Faith (CDF) teaches that techniques involving gametes (like IVF or artificial insemination) which separate the marriage act from procreation are immoral.
2. Dignitas Personae (2008): This document from the Congregation for the Doctrine of the Faith specifically outlines the church’s stance on gene therapy and stem cells, including the prohibition of procedures that manipulate or destroy embryos, including genetic engineering, cloning, and the freezing of embryos. 

Now, in practice, this is a distinction without a difference, as every parent alive would simply apply the genetic solution to their children either in utero or shortly after birth, so functionally, every subsequent generation of human beings is going to be healed of the genetic disease regardless. It's just that the Church has decided the more efficient way of doing it (gamete change) is sinful while the less efficient way (somatic cell therapy) is morally acceptable. 

HIV Cure

The Amsterdam UMC team used CRISPR-Cas gene editing—often described as molecular scissors—to target conserved (stable across strains) sequences in the HIV genome. Key findings from their 2024 work (presented ahead of the European Congress of Clinical Microbiology and Infectious Diseases):

• They employed systems like saCas9 (a smaller Cas9 variant from Staphylococcus aureus) and tested cjCas9.
• With one guide RNA (gRNA), saCas9 could inactivate HIV.
• With two gRNAs, it excised (cut out) segments of the integrated viral DNA from the host chromosome in infected T cells.
• In cell culture experiments, this led to complete elimination of infectious HIV, with no detectable viral traces or rebound. The edited cells also resisted reinfection when re-exposed to the virus.

Approved Gene Therapies (Viral Vector-Based Gene Addition or Delivery)

These deliver a functional copy of the defective gene, often using adeno-associated virus (AAV) or lentiviral vectors.

• Leber Congenital Amaurosis (LCA) Type 2 / Inherited Retinal Dystrophy due to RPE65 mutations Treatment: Luxturna (voretigene neparvovec) — in vivo AAV gene therapy injected into the eye. Outcome: Restores vision or slows vision loss; first in vivo gene therapy approved (2017/2018). Improves light sensitivity and navigation in patients with this rare blinding disorder.
• Spinal Muscular Atrophy (SMA), especially Type 1 (infantile-onset) Treatment: Zolgensma (onasemnogene abeparvovec) — in vivo AAV9 gene therapy delivering functional SMN1 gene. Outcome: One-time IV infusion; enables motor milestone achievement, prolongs survival, and reduces need for ventilation in treated infants. Approved for young children.
• Hemophilia A (severe, Factor VIII deficiency) Treatment: Roctavian (valoctocogene roxaparvovec) — in vivo AAV5 liver-directed gene therapy. Outcome: Sustained production of Factor VIII, reducing bleeding episodes and need for prophylactic factor replacement.
• Hemophilia B (Factor IX deficiency) Treatment: Hemgenix (etranacogene dezaparvovec) — in vivo AAV-based gene therapy. Outcome: Long-term Factor IX expression, significantly reducing bleeding rates.
• Duchenne Muscular Dystrophy (DMD) Treatment: Elevidys (delandistrogene moxeparvovec) — in vivo AAV gene therapy delivering a micro-dystrophin gene. Outcome: Improves muscle function and slows disease progression in eligible ambulatory patients (approved with accelerated/expanded indications).
• Recessive Dystrophic Epidermolysis Bullosa (RDEB, a severe skin blistering disorder) Treatment: Vyjuvek (beremagene geperpavec) or similar topical gene therapy. Outcome: Promotes wound healing and skin integrity by delivering functional COL7A1 gene.

Other notable approvals include therapies for aromatic L-amino acid decarboxylase (AADC) deficiency (Kebilidi) and certain immunodeficiencies like Wiskott-Aldrich syndrome (recent approvals for autologous gene-corrected stem cells).

CRISPR-Based Genome Editing Therapies (Primarily Ex Vivo)

These involve editing patient cells outside the body (ex vivo) or, in emerging cases, directly in the body (in vivo).

• Sickle Cell Disease (SCD) Treatment: Casgevy (exagamglogene autotemcel, exa-cel) — ex vivo CRISPR-Cas9 editing of hematopoietic stem cells to reactivate fetal hemoglobin (by editing BCL11A). Also Lyfgenia (lentiviral gene addition, non-CRISPR). Outcome: First CRISPR-approved therapy (UK 2023, FDA 2023). Eliminates or dramatically reduces vaso-occlusive crises (painful episodes); many patients become crisis-free with sustained fetal hemoglobin production. Functional cure in a high percentage of treated patients.
• Transfusion-Dependent Beta-Thalassemia (TDT) Treatment: Casgevy (same as above). Also earlier lentiviral therapies like Zynteglo (betibeglogene autotemcel). Outcome: Most patients become transfusion-independent with normalized or near-normal hemoglobin levels for years post-treatment.

Primary Success: OTOF-Related Deafness (DFNB9 / Auditory Neuropathy Spectrum Disorder)

• Cause: Mutations in the OTOF gene prevent proper function of otoferlin, a protein essential for transmitting sound signals from inner ear hair cells to the auditory nerve. Affected individuals are typically born profoundly deaf (or with severe hearing loss) in both ears.
• Therapy Approach: In vivo AAV (adeno-associated virus) gene therapy delivers a functional copy of the OTOF gene directly into the inner ear (usually via intracochlear injection under anesthesia). Because the OTOF coding sequence is large, some therapies use a dual-AAV vector system to split and reassemble the gene.

Key Clinical Results (as of 2025–2026)

• DB-OTO (Regeneron / Decibel Therapeutics):
  • In the pivotal CHORD trial (published in NEJM, October 2025), 12 children with OTOF-related profound deafness received a single infusion.
  • Outcomes: 11 of 12 participants (92%) showed clinically meaningful hearing improvements; 9 of 12 met the primary endpoint (average pure-tone audiometry threshold ≤70 dB HL at week 24). Three achieved near-normal or normal hearing sensitivity. Six could hear soft speech without devices. Improvements were often seen within weeks, with stability or further gains up to 72 weeks in follow-up. Some participants showed improved speech perception.
  • Regeneron has indicated plans to seek regulatory approval (potentially making this the first approved gene therapy for hearing loss).
• Other OTOF trials (China-led, Akouos/Lilly AK-OTOF, Sensorion SENS-501, and collaborations involving Harvard/Mass Eye and Ear, CHOP, etc.):
• Multiple independent trials (starting 2022–2024) restored hearing in profoundly deaf children aged 1–7 (and some older patients up to ~24 years).
• Examples: Five of six children in a bilateral treatment trial gained the ability to recognize speech, understand conversation (including in noise for some), and locate sound sources. One child went from complete deafness to mild-moderate loss and could hear voices/ambient sounds for the first time.
• Improvements often progressive over months; many achieved functional hearing sufficient to avoid or reduce reliance on cochlear implants.
• Benefits observed in both children and young adults, with rapid onset (often within 1 month) and sustained effects.

CRISPR/Gene Editing for Hearing Loss

• Preclinical/Animal Success: CRISPR-Cas9 has been used successfully in mouse models to:
  • Disrupt dominant-negative mutations (e.g., in Tmc1 "Beethoven" mice) and preserve or restore hearing.
  • Prevent progressive hearing loss or protect against noise-induced damage.
  • Improve outer hair cell survival in certain genetic models.
• Human Status: No widespread clinical success or approvals yet for CRISPR-based treatments of deafness. Early research and consensus statements note potential, but trials remain preclinical or very early-stage. One area of interest is progressive adult-onset genetic deafness (e.g., DFNA41 models), where editing showed promise in animals and patient-derived cells.

Approved Gene and Cell Therapies for Cancer

The most established successes use CAR-T cell therapy, an ex vivo gene therapy approach. Patient T cells are extracted, genetically modified (often via viral vectors) to express a chimeric antigen receptor (CAR) that targets cancer cells, expanded, and reinfused.

Approved CAR-T therapies (as of 2026) include:

• Kymriah (tisagenlecleucel): For relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and certain large B-cell lymphomas. Many patients achieve complete remission, with some durable responses lasting years.
• Yescarta (axicabtagene ciloleucel) and Breyanzi (lisocabtagene maraleucel): For large B-cell lymphoma and other non-Hodgkin lymphomas. High rates of complete response in refractory cases.
• Tecartus (brexucabtagene autoleucel): For mantle cell lymphoma and B-cell ALL.
• Abecma (idecabtagene vicleucel) and Carvykti (ciltacabtagene autoleucel): For relapsed/refractory multiple myeloma, targeting BCMA. Significant remission rates, including stringent complete responses in heavily pretreated patients.

Other approved gene-based cancer therapies:

• Provenge (sipuleucel-T): Autologous cellular immunotherapy (gene-modified dendritic cells) for prostate cancer.
• Imlygic (talimogene laherparepvec, T-VEC): Oncolytic virus gene therapy injected into melanoma lesions to stimulate immune response.
• Adstiladrin (nadofaragene firadenovec): Adenoviral vector delivering interferon-alpha for non-muscle invasive bladder cancer.

Long-term outcomes: Some early CAR-T patients (treated around 2010) remain cancer-free over a decade later, with the modified cells persisting as "living drugs." Complete remissions have been documented in refractory leukemias and lymphomas, allowing patients to achieve durable disease-free status.

CRISPR and Gene Editing in Cancer

CRISPR-Cas9 and related editing tools (e.g., base editing) are used ex vivo to enhance immune cells or disrupt cancer-promoting genes. No broad CRISPR approvals for cancer exist yet, but clinical results are encouraging:

• CRISPR-edited CAR-T or TIL therapies: Trials show safety and responses in blood cancers and solid tumors. For example, a University of Minnesota trial using CRISPR to knock out the CISH gene in tumor-infiltrating lymphocytes (TILs) for advanced gastrointestinal cancers resulted in halted tumor growth in several patients and a complete response (tumors disappeared and did not return for over two years) in one case.
• Base-edited CAR-T (e.g., BE-CAR7): For T-cell acute lymphoblastic leukemia (T-ALL), an aggressive "incurable" blood cancer. In trials, 82% of patients achieved deep remission (enabling stem cell transplant), and 64% remained disease-free at follow-up (some over three years).
• Preclinical/early work: CRISPR to reverse chemotherapy resistance (e.g., editing NRF2 in head and neck or lung cancers) or enhance CAR-T persistence against solid tumors.

In vivo approaches (direct delivery without removing cells) are emerging, including AAV-based and lentiviral in vivo CAR-T reprogramming, with early signs of efficacy in leukemia and myeloma models.

The "non-biologist" Australian man who used AI protein-folding software to cure his dog of cancer.