Gene-based therapies

The treatment of most genetic disorders is based on conventional therapeutic approaches.

Gene therapy is an umbrella term for a number of techniques aimed at treating or preventing genetic disease.

The mechanisms of gene-based therapies include:

·       replacing the mutated copy of a gene with a functional copy, restoring protein function.

·       inactivating a mutated gene that has impaired function (‘knocking out’)

·       introduction of a new gene for the production of a beneficial protein.

There are a variety of types of gene therapy products, including:

1.   Plasmid DNA: Circular DNA molecules can be genetically engineered to carry therapeutic genes into human cells.

2.  Viral vectors: Viruses have a natural ability to deliver genetic material into cells, and therefore some gene therapy products are derived from viruses. Once viruses have been modified to remove their ability to cause infectious disease, these modified viruses can be used as vectors (vehicles) to carry therapeutic genes into human cells.

3.  Bacterial vectors: Bacteria can be modified to prevent them from causing infectious disease and then used as vectors (vehicles) to carry therapeutic genes into human tissues.

4.    Human gene editing technology: The goals of gene editing are to disrupt harmful genes or to repair mutated genes.

5.   Patient-derived cellular gene therapy products: Cells are removed from the patient, genetically modified (often using a viral vector) and then returned to the patient.

Vectors are genetically engineered to allow the introduction of the new gene.

Different viral vectors act in different ways, for example, retroviruses integrate their own genetic material, including the new gene, into the chromosome in the human cell, whereas adenovirus introduces DNA into the nucleus without chromosomal integration.

There are still many technical and safety issues to be resolved.

Gene therapy products are being studied to treat diseases including cancer, genetic diseases, and infectious diseases.

In the U.S., FDA-approved gene therapy products include:

·     Axicabtagene ciloleucel (Yescarta): This gene therapy is for adults who have certain types of large B-cell lymphoma that don't respond to treatment.

·      Onasemnogene abeparvovec-xioi (Zolgensma): This gene therapy can be used to treat children under age 2 who have spinal muscular atrophy.

·      Talimogene laherparepvec (Imlygic): This gene therapy is used to treat certain types of tumors in people with melanoma that come back after surgery.

·    Tisagenlecleucel (Kymriah): This gene therapy is for people up to 25 years old who have follicular lymphoma that has come back or isn't responding to treatment.

·       Voretigene neparvovec-rzyl (Luxturna): This gene therapy is for people 1 year old and older who have a rare inherited type of vision loss that can lead to blindness.

·      Exagamglogene autotemcel (Casgevy): This gene therapy is for treating people 12 years and older with sickle cell disease or beta thalassemia who meet certain criteria.

·       Delandistrogene moxeparvovec-rokl (Elevidys): This gene therapy is for children ages 4 through 5 years who have Duchenne muscular dystrophy and a flawed DMD gene.

·       Lovotibeglogene autotemcel (Lyfgenia): This gene therapy is for people 12 years and older with sickle cell disease who meet certain criteria.

·     Valoctocogene roxaparvovec-rvox (Roctavian): This gene therapy is for adults with severe hemophilia A who meet certain criteria.

·     Beremagene geperpavec-svdt (Vyjuvek): This is a topical gene therapy for treating wounds in people 6 months and older who have dystrophic epidermolysis bullosa, a rare inherited condition that causes fragile, blistering skin.

·    Betibeglogene autotemcel (Zynteglo): This gene therapy is for people with beta thalassemia who need regular transfusions of red blood cells.

Clinical trials of gene therapy in people have helped treat several diseases and disorders, including:

·       Severe combined immunodeficiency.

·       Hemophilia and other blood disorders.

·       Blindness caused by retinitis pigmentosa.

·       Leukemia.

·       Inherited neurological disorders.

·       Cancer.

·       Heart and blood vessel diseases.

·       Infectious diseases.

Early gene therapy was limited to somatic cells, and germline gene therapy remains controversial. While germline gene therapy could prevent disease in future generations, it might also affect the fetus in unknown ways, or have long-term consequences which are as yet unknown.

An increasing understanding of the molecular mechanisms underlying the pathophysiology of many genetic conditions has also led to new targeted drug treatments in several conditions, including enzyme replacement therapy for certain inborn errors of metabolism and mTOR inhibitor therapy in tuberous sclerosis.