Viral Vectors
Adenoassociated viruses (AAVs):
Companies: MeiraGTx (optimization of AAV vectors and promoter sequences. Riboswitch technology that is designed for control of gene expression by oral small molecules).
Introduction:
AAVs is one of the most commonly used viral vectors for in vivo gene therapies. However, AAV based treatments often cause a short-term heptic immune response. This can be dampened with the use of antinflammatory medications such as steroids. A number of methods have been prosed to prevent immune detection of gene therapies, including the use of lipid nanoparticles for gene delivery or engineering viral capsids to evade recognition for patients’ antibodies. (Rsellini, BioProcess International, vlume 20, number 4, april 2022.
An AAV’s protein shell surrounds and protects its small (25 nm) single stranded DNA genome of about 4.7 Kb. That genome contains just three genes; rep (for replication), cap (for the capsid) and nap 9 for particle assembly). Lacking viral DNA, recombinant AAV (rAAV) is essentially a protein based nanoparticle engineered to pass through cell membranes, through which it carries and delivers a therapeutic DNA “cargo” into the cell’s nucleus. Because AAVs cannot replicate without outside help, they provide a safe vehicle to drive long term transgene expression after single infection. (BioProcess international, 21(1-2) 2023).
Applications:
–-Duchenne Muscular Dystrophy (DMD):
DMD is a rare genetic muscle disease. It occurs primarily in males, although females can be affected and they also pass the genetic mutation onto their children. DMD affects an estimated 12,000 to 15,000 people in the U.S. and 25,000 in Europe. DMD is the most common childhood-onset form of muscular dystrophy. Loss of strength and function typically first appear between 3 and 5 years of age. DMD results from a genetic mutation in the DMD gene on the X chromosome. This gene regulates the production of dystrophin, a protein essential to healthy muscle development and function. In people with DMD, dystrophin levels are absent or nearly absent, which causes permanent damage to muscle cells. See Dyne
—-Elevidy (delandistrogen moxeparvovec rokl): is an adeno-assocaited virus vector based gene theurapy of ambulatory pediatric patients age 4-12 with Duchenne muscular dystrophy with a confirmed mutation in the Duchenne muscular dystrophy gene. It is designed to deliver into the body a gene that leads to production of Elevidys micro-dystrophin that contains selected domains of the dystrophin protein present in normal muscle cells. The accelerated US Food and Drug Administration (FDA) approval of delandistrogene moxeparvovec was based on data from a randomized clinical trial that established that delandistrogene moxeparvovec increased the expression of the Elevidys micro-dystrophin protein observed in delandistrogene moxeparvovec-treated individuals aged four to five years with Duchenne muscular dystrophy.
–Spinal Muscular Atrophy:
SMA is a neurological disorder caused by a mutation in the SMN1 gene, which leads to a decrease in the SMN protein, a protein encessary for the survival of motor neurons.
—-Zogensma (Onasemnogene abeparvovec) (Novartis): is a gene therpay used to treat pediatric patients less than two years of age with spinal muscular atrophy with biollelic mutations in the survival motor nueron 1 gene. It involves a 1 time infusion of the drug into a vein. Zogensma is a biological drug which uses AAV9 viral capsids containing an SMN1 transgene.
–-REE65 Mediated Retinal Dystrophy:
Lentiviral Gene Therapies
Companies: Avrobio (AVRO: develops gene therapies to treat lysosomal storage diseases)
Lentiviral vecors are used mosly for ex vivo gene therpapy and are designed to deliver stable and durable integration of transgenes into a patient’s hematopoietic stem cells. The prcoess begins with harvesting CD34 stem cells form a patient. These cells are modified by using a lentiviral vector to insert a transgene that will enable production of a functional protein. The modified stem cells are infused back into the patient, where they engraft in the patient’s bond marrow. The cells divide to produce daughter cells, all carrying the transgene for the functional protein needed by those cells. In some cases, a protein is secreted to help other cells that have the defective gene, a process called cross-correction.
–Luxturna (voretigene neparvovec-rzyl): is an deno-assocaited virus vector based gene therpay approved for patients with confirmed biallelic RPE65 mutation-assocaited retinal dystrophy. Patients must have viable retinal cells as determiend by the treating physician(s). The gene therapy is not a cure for the condition, but substantially improves vision in those treated.