How Do Gene Therapies, Neurologics Work?

Gene therapies are treatments of inherited diseases or disorders caused by mutations or absence of certain genes. Neurologic gene therapies are used to treat genetic disorders that affect neurological functions. Gene therapies involve the transfer of engineered genetic material to take over the function of the mutated or missing gene.

Abnormal functioning or absence of genes results in deficiency or absence of the proteins and enzymes encoded by these genes, which disrupts normal cellular functions and leads to disease. By introducing the specific gene into the DNA, gene therapy restores the production of the necessary proteins and enzymes to prevent disease progression.

Gene therapy involves the production of functional genetic material by DNA recombinant technology. Genes directly introduced into a cell do not usually function, so the genes are delivered using a viral vector that has been made harmless by modifying its DNA to prevent replication and its disease-causing capability.

Newer techniques of gene therapies are being researched to develop other ways to deliver the genetic material instead of using a virus vector which can sometimes induce a severe immune response or cause cancer. These new techniques use extremely tiny nanoparticles to deliver the genetic material into the cells.

Currently, there are three neurologic gene therapies approved by the FDA to treat three different genetic disorders:

Atidarsagene autotemcel (Lenmeldy): Lenmeldy is used to treat metachromatic leukodystrophy (MLD), a disease caused by a mutation in the arylsulfatase-A (ARSA) gene, which results in accumulation of fats known as sulfatides in the brain and other organs. Sulfatide deposits destroy the myelin sheath that protects nerve fibers, affecting nerve functions.

Lenmeldy is prepared from the patient’s own blood-forming (hematopoietic) stem cells (HSCs) which are extracted from their blood in a procedure known as apheresis. HSCs that are positive for CD34 are then isolated. CD34 is a substance in the stem cells that functions as adhesion factor between cells and promotes the proliferation and differentiation of HSCs.

Functional copies of ARSA genes are inserted into the CD34-positive HSCs using a lentiviral vector (LVV). These stem cells get grafted into the bone marrow and produce more HSCs that have functional ARSA genes which produce ARSA enzyme necessary for breaking down the sulfatides.

delandistrogene moxeparvovec (Elevidys): Elevidys is used to treat children with Duchenne muscular dystrophy (DMD), a severe neuromuscular disease caused by mutations in the DMD gene that results in a lack of functional dystrophin. Dystrophin is a protein vital for the integrity of muscle cells and without this protein, muscles break down.

Elevidys is a recombinant gene therapy that delivers an artificial gene (transgene) that produces a micro-dystrophin protein consisting of selected domains of dystrophin found in normal muscle cells. The transgene is carried within an adeno-associated virus (AAV) serotype rh74 (AAVrh74) viral protein shell (capsid).

elivaldogene autotemcel (Skysona): Skysona is used to treat cerebral adrenoleukodystrophy (CALD), a neurological disease caused by mutations in the ABCD1 gene that results in accumulation of very long-chain fatty acids (VLCFAs) in the brain, resulting in loss of the myelin sheath of nerve fibers.

Skysona is prepared by inserting functional transgene copies of the ABCD1 gene into the patient’s own CD34-positive HSCs using a Lenti-D lentiviral vector. The HSCs engraft in the bone marrow and produce more progenitor HSCs that can differentiate into various type of cells including monocytes.

Monocytes produced by the progeny of the introduced HSCs possess the ABCD1 gene and are capable of producing adrenoleukodystrophy protein (ALDP). ALDP is a protein that degrades the VLCFAs and helps slow down or prevent further loss of myelin (demyelination) and nerve inflammation.

Gene therapies, neurologics are suspensions administered as a single-dose, single-time intravenous infusion to treat certain neurological disorders in pediatric patients. The FDA-approved uses of gene therapies, neurologics are:

atidarsagene autotemcel (Lenmeldy): Treatment of children with pre-symptomatic late infantile (PSLI), pre-symptomatic early juvenile (PSEJ) or early symptomatic early juvenile (ESEJ) metachromatic leukodystrophy (MLD).

delandistrogene moxeparvovec (Elevidys): Treatment of ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene.

This indication has been approved based on the expression of Elevidys micro-dystrophin in the skeletal muscle of treated patients. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

elivaldogene autotemcel (Skysona): To slow the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy (CALD). Early, active CALD refers to asymptomatic or mildly symptomatic (neurologic function score [NFS] that is 1 or lower) boys who have gadolinium enhancement on brain magnetic resonance imaging (MRI) and Loes scores of 0.5-9.

The above indication is approved based on 24-month Major Functional Disability (MFD)-free survival. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

Common side effects of gene therapies, neurologics include the following:

Atidarsagene autotemcel (Lenmeldy)

• Low neutrophil count with fever (febrile neutropenia)
• Risk of neutrophil engraftment failure
• Delay in platelet engraftment
• Oral inflammation (stomatitis)
• Respiratory tract infections
• Device-related infection
• Gastroenteritis
• Other viral infections
• Serious infection
• Rash
• High temperature (pyrexia)
• Liver enlargement (hepatomegaly)
• Blood clots (thrombosis)
• Brain inflammation (encephalitis)
• Veno-occlusive disease
• Hypersensitivity reactions
• Risk of cancer

Delandistrogene moxeparvovec (Elevidys)

• Nausea
• Vomiting
• Elevation of liver enzymes
• Acute serious liver injury
• Pyrexia
• Low platelet count (thrombocytopenia)
• Immune-related muscle inflammation (myositis)
• Inflammation of the heart muscle (myocarditis)

Elivaldogene autotemcel (Skysona)

• Inflammation of mucous membranes (mucositis)
• Nausea
• Vomiting
• Abdominal pain
• Constipation
• Diarrhea
• Decrease in appetite
• Blood disorders including:
• Low white blood cell count (leukopenia)
• Low count of lymphocytes (lymphopenia)
• Thrombocytopenia
• Low red blood cell count (anemia)
• Neutropenia
• Febrile neutropenia
• Low count of all types of blood cells (pancytopenia)
• Low blood potassium (hypokalemia)
• Hair loss (alopecia)
• Rash
• Itching (pruritus)
• Excessive skin pigmentation
• Pyrexia
• Headache
• Anxiety
• Nasal bleeding (epistaxis)
• Mouth and throat (oropharyngeal) pain
• Cough
• Rapid heart rate (tachycardia)
• High blood pressure (hypertension)
• Blurred vision
• Infusion-related reaction
• Hypersensitivity reactions
• Blood-related malignancy
• Serious infections
• Prolonged cytopenias
• Risk of neutrophil engraftment failure
• Delay in platelet engraftment

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of gene therapies, neurologics include:

• atidarsagene autotemcel
• delandistrogene moxeparvovec
• delandistrogene moxeparvovec-rokl
• Elevidys
• elivaldogene autotemcel
• Lenmeldy
• Skysona