A virus is a tiny, microscopic structure consisting of a strand of DNA or RNA surrounded by a simple coating of proteins and/or lipids. Unlike other disease-causing microbes such as bacteria, most scientists do not consider viruses to be living organisms as they need a host to reproduce, like parasites. Viruses are only able to reproduce by infecting cells and inserting their genetic material into the host cell. This alters the cell so that it will produce more copies of the virus, which will in turn infect more cells.
This process causes viral diseases like the common cold, the flu, or COVID-19. However, researchers have discovered methods of using viruses to treat various diseases. To accomplish this, the original DNA/RNA is removed from a virus and replaced with genetic material designed to have a therapeutic effect.
By taking advantage of a virus’ natural infectious abilities, these “viral vectors” enable the delivery of gene therapies directly into patients’ cells.
AMT-162
uniQure a biotech company, is currently developing an experimental treatment option for adults with SOD1 related ALS called AMT-162, which recently began a phase 1/2 clinical trial. The company specializes in the development of gene therapies using adeno-associated virus (AAV) vectors. AAVs are a type of virus suitable for this use because they readily infect human cells but, even in their natural state, are known not to cause disease in humans. In addition to AMT-162, uniQure also has an AAV gene therapy approach for C9orf72-related ALS that is currently in preclinical development.
“These viruses are used as vectors – packages that deliver the gene therapy candidate being investigated,” says Dr. Brenda Vincenzi, uniQure’s Executive Director of Clinical Development. “They are generally very good at finding their way into cells, which is where we want to deliver the investigational therapy. To ensure that the vectors are not infectious anymore, but they can still get into the target cells – in the case of ALS, motor neuron cells, the viral genes are removed.”
“Even before the viral gene has been removed,” adds Dr. Ying Poi Liu, uniQure’s Director of Global Research, “it is important to note that the wild type, or natural, AAV have rarely been found to cause any kind of disease.”
In cases of SOD1-related ALS, mutations in the SOD1(superoxide dismutase 1) gene cause the production of mutated SOD1 proteins that misfold and clump up (aggregate), thereby interfering with healthy cell function and causing toxicity in motor neurons. AMT-162 is an investigational AAV gene therapy designed to deliver therapeutic genetic material to motor neurons causing the degradation of SOD1 mRNA – the molecules that carry information to make the SOD1 protein, which is thought to stop the production of the toxic SOD1 proteins.
“By silencing the gene encoded products of mRNA,” says Dr. Vincenzi, “the production of the toxic SOD1 proteins associated with ALS could be reduced, hopefully leading to the halting or slowing of disease progression.”
AMT-162 EPISOD1 Clinical Trial
Recently, the first site in uniQure’s phase 1/2 trial, named EPISOD1, began recruiting participants with SOD1-related ALS. The study will enroll between six and twelve participants, who will receive one of three escalating doses levels of the drug through an intrathecal injection. A second cohort of six to eight participants will later be treated with the dose selected from the initial three.
“The primary objectives of this study are safety and tolerability,” says Dr. Vincenzi. “We will also take an exploratory and initial look at efficacy, using biomarkers like neurofilament light chain (NfL) and SOD1 protein and clinician and patient-reported outcomes measures like the ALSFRS-R, to help us design subsequent studies.”
While the trial is currently only recruiting in California, sites will soon be opening in Illinois, Massachusetts, New York, and Pennsylvania and other US States. After a screening period, participants will be administered AMT-162 in a single dose in the hospital setting. To address the potential risk of adverse side effects caused by the immune system’s reaction to the administration, participants will also be given immunosuppressive drugs before and after receiving AMT-162. Afterwards, participants will complete five years of safety follow-up to monitor their condition and look for side effects. These follow-up visits will occur every three months for the first year, every six months for the second year, and annually for the last three years.
One important enrollment requirement for interested participants to note, says Dr. Vincenzi, is that the study asks that enrollees refrain from taking tofersen, a recently approved gene therapy marketed in the US under the brand Qalsody by the company Biogen.
People with SOD1-related ALS who are taking tofersen may still enroll in the trial if their last dose of tofersen was at least 20 weeks prior to the first screening visit in the EPISOD1 study. They may also resume or begin taking tofersen with a minimal interval of six months after the administration of AMT-162.
For more information about the AMT-162 trial, including sites, inclusion and exclusion criteria, and contact information, visit the ALS Trial Navigator.
What to Do Next:
