The only drug that has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of Rett syndrome, a rare genetic neurological and developmental disorder, was almost exactly a year ago. Although there is no cure for Rett syndrome, ongoing drug trials for gene therapies aim to expand treatment options.

In most cases, the condition is caused by a mutation in the MECP2 gene, which is present on the X chromosome. Rett syndrome affects one in 10,000 female births in the U.S., according to the National Organisation for Rare Disorders. The MECP2 gene codes for a protein that is essential to brain development, and so, the mutation leads to the nerve cells in the brain not performing their functions properly. Most people with Rett syndrome don’t inherit the disease, and in nearly all cases, the mutations occur randomly.

The most recent drug that was cleared to treat the disease is trofinetide, which was approved in March last year.

Trofinetide for the treatment of Rett syndrome

The drug, which is developed by Acadia Pharmaceuticals and sold under the brand name Daybue, is a synthetic version of a naturally occurring molecule known as the tripeptide glycine-proline-glutamate (GPE). Although trofinetide’s exact mechanism is not known, it has been shown to improve the branching of dendrites as well as synaptic plasticity signals. A dendrite is the part of a nerve cell shaped like the branches of a tree that receives electrical signals from another neuron’s axon terminal end, and passes it on to the rest of the nerve cell. The branching of these dendrites is crucial to creating new synapses, which are the joints where neurons meet.

Synaptic plasticity is the ability of these junctions in the nerve cells to modify themselves based on how active they become. These two factors are key to controlling inflammation and overactivity of the nerve cells.

In the clinic, trofinetide was evaluated in patients aged between five and 20. The drug’s efficacy was tested in patients based on the changes in two scales: the Rett Syndrome Behaviour Questionnaire (RSBQ) and the Clinical Global Impression-Improvement (CGI-I) scales. The RSBQ total score, which studies a range of symptoms like facial expressions, eye gaze, hand movements, repetitive behaviors, breathing, night-time behaviours, and mood, evaluated by the caregiver, was found to be statistically significant at the end of 12 weeks.

The CGI-I score, which assesses whether the patient’s condition has improved or worsened, was 0.003, in the phase 3 trial that led to the FDA nod. The score is rated on a scale from one to seven, where, the lower the score, the greater the improvement.

However, it costs $9,495 for a 450 ml bottle of trofinetide in the U.S., excluding insurance. The 200 mg/ml dosage depends on the weight of the patient, varying from 25 ml to 60 ml, twice daily. This would cost around $375,000 out-of-pocket in a year for one person, most of which is covered by Medicaid.

Taysha’s gene therapy for Rett syndrome advances

While trofinetide helps manage symptoms in children, it doesn’t cure the disease. That’s why if a gene therapy were to make a debut in the market, it would be a significant move for the Rett syndrome community. Currently in the works to make that happen is a team of researchers at American biotech Taysha Gene Therapies.

When it comes to MECP2, too little expression leads to disease, while too much causes toxic effects. So, the strategy revolves around hitting the sweet spot of gene expression – not too little, not too much, but just the right amount. This is done by regulating the gene’s expression on a cell-by-cell basis.

The candidate TSHA-102 is designed to mediate levels of MeCP2 proteins in the central nervous system without the risk of overexpressing the gene. This would mean increasing MeCP2 levels in protein-deficient cells. Having shown safe levels of increase in mice, it has since moved to the clinic and the first patient was dosed in January in a trial for children aged between five and eight.

Another ongoing trial focuses on adolescents and adults with Rett syndrome, for which it has been greenlit to increase dosage levels to determine the best dose of TSHA-102, by the FDA. Having been awarded fast track designation by the FDA and orphan drug designation by the European Commission, this could speed things up for Taysha, and the drug could reach regulators sooner. The biotech also pulled a private investment in public equity (PIPE) deal last year to support TSHA-102’s development.

A new cost-effective way to develop gene therapies for Rett syndrome?

Researchers in Shanghai, China are also looking to advance gene therapy to treat the disease. But unlike many other gene therapies that deliver the genes through intravenous infusion, which has been linked to liver toxicity, this team of scientists has taken to delivering via direct injection in an attempt to eliminate this side effect.

Moreover, this method does not involve altering the cells in a lab before injecting them, thereby making it more cost-effective. This is done by enveloping normal MECP2 genes into a viral vector, which is then injected. Using CRISPR/Cas9 gene editing, the gene was knocked out in mice, in order to simulate the gene expression observed in people with Rett syndrome. When the mice were treated, protein levels in the brain rose. A cytomegalovirus early enhancer/chicken beta actin (CAG) promoter – used to drive transgene expression – helped enhance protein expression.

However, the levels were unequal, as the hypothalamus – the region in the brain that releases hormones and acts as the body’s smart control – took well to the treatment, whereas the hippocampus – the region associated with memory and learning – had the lowest levels of the protein.

Although there is still much to be done, this has the potential to bring a more affordable gene therapy to the market.

Other ongoing Rett syndrome clinical trials

Clinical-stage company Neurogene is also on a quest to treat Rett syndrome with its gene therapy. Its phase 1/2 candidate NGN-401 is being tested in a trial for girls with Rett syndrome. Like the preclinical candidate being tested in China, as well as Taysha’s TSHA-102, Neurogene’s therapy is also packaged in an adeno-associated virus (AAV) so that effective gene delivery can take place. The therapy has been granted orphan drug, rare pediatric disease, and fast track designations, to accelerate approval.

Also in the clinic is Australia-based Neurotech International’s NTI164, which is designed to alleviate Rett syndrome. The cannabis-derived drug candidate NTI164 has been found to tone down inflammation, a major symptom of the disease. By suppressing inflammatory cytokines, nerve cells can function better, which is central to controlling the symptoms. The biopharma has begun a phase 1/2 trial to test the drug in 14 children.

A long road ahead for Rett syndrome treatments

While these biopharmas seem like they may be onto something, the Rett syndrome community has been let down in the past when drugs failed in the clinic. Only recently, Anavex Life Sciences’ much-awaited Rett syndrome drug failed a phase 2/3 trial. The drug, which is designed to bind to the sigma-1 receptor and reduce protein folding, did not meet statistical significance. Anavex blamed this on a high placebo effect, stating that it may have “masked the compound’s therapeutic effect,” according to a press release. However, the drugmaker isn’t giving up just yet, and is looking to further assess the drug.

Previously, Swiss multinational Novartis had also pulled the plug on its preclinical gene therapy, citing that it did not support a path towards clinical trials. And so did Newron Pharmaceuticals, which abandoned a phase 3 trial when its receptor agonist didn’t exhibit efficacy in a phase 2 study.

While curing a genetic condition has proven to be rather tough, for rare diseases like Rett syndrome, trials aren’t held often because finding people that fit the specific criteria of the trial is not easy. Plus, patient populations are widely dispersed and vary based on their symptoms, how the disease manifests itself, and what prior treatment each patient has undergone. Moreover, the limited number of patients makes it expensive to hold trials, and biopharmas end up scrapping trials altogether because of this.

Nevertheless, as ongoing trials move ahead, and more drug candidates receive orphan drug designations, there is hope for the Rett syndrome community as the much-anticipated drugs that address the root cause of the disease – the genetic mutations – gain traction.