**Historical Development**:
– Gene therapy conceptualized in the 1960s.
– First successful genetic alteration in mammalian cells reported in 1961.
– Clinical successes since 2006 renewed interest in gene therapy.
– FDA jurisdiction over gene therapy announced in 1986, with evolving definitions.
– Gene therapy attempts date back to 1980, with the first successful trial in 1990.
**Therapeutic Applications**:
– Gene therapy used to treat diseases like Leber’s congenital amaurosis and Parkinson’s.
– Commercial gene therapies like Gendicine, Glybera, and Neovasculgen have been approved.
– Focus on diseases caused by single-gene defects.
– Gene editing shows potential for treating genetic diseases, viral diseases, and cancer.
– Multiple delivery techniques explored for administering therapeutic genes.
**Regulatory Approval and Market Impact**:
– Gendicine was the first gene therapy approved in 2003.
– Several gene therapy drugs approved targeting various diseases.
– Companies investing significantly in gene therapy research and development.
– Approval of gene therapy drugs like Glybera and Kymriah marked milestones in medical treatment.
– Gene therapy promising for rare inherited disorders and genetic diseases.
**Approaches and Techniques**:
– Different methods like AAVs, lentiviruses, and ASO/siRNA used for gene insertions.
– Bone marrow and organ transplants can introduce foreign DNA.
– Direct DNA editing techniques like zinc finger nucleases and CRISPR being used.
– Strategies focus on expressing needed proteins or disrupting defective genes.
– Gene therapy classified broadly as gene addition or replacement in targeted cells.
**Challenges and Concerns**:
– Immune response challenges in gene therapy.
– Problems with viral vectors including toxicity and targeting issues.
– Insertional mutagenesis risks and challenges in gene integration.
– Multigene disorders complicating gene therapy approaches.
– Historical concerns and moratoriums on human germline modification.
Gene therapy is a medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells.
The first attempt at modifying human DNA was performed in 1980, by Martin Cline, but the first successful nuclear gene transfer in humans, approved by the National Institutes of Health, was performed in May 1989. The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990. Between 1989 and December 2018, over 2,900 clinical trials were conducted, with more than half of them in phase I. In 2003, Gendicine became the first gene therapy to receive regulatory approval. Since that time, further gene therapy drugs were approved, such as Glybera (2012), Strimvelis (2016), Kymriah (2017), Luxturna (2017), Onpattro (2018), Zolgensma (2019), Abecma (2021), Adstiladrin, Roctavian and Hemgenix (all 2022). Most of these approaches utilize adeno-associated viruses (AAVs) and lentiviruses for performing gene insertions, in vivo and ex vivo, respectively. AAVs are characterized by stabilizing the viral capsid, lower immunogenicity, ability to transduce both dividing and nondividing cells, the potential to integrate site specifically and to achieve long-term expression in the in-vivo treatment. ASO / siRNA approaches such as those conducted by Alnylam and Ionis Pharmaceuticals require non-viral delivery systems, and utilize alternative mechanisms for trafficking to liver cells by way of GalNAc transporters.
Not all medical procedures that introduce alterations to a patient's genetic makeup can be considered gene therapy. Bone marrow transplantation and organ transplants in general have been found to introduce foreign DNA into patients.