Scientists provide first evidence that the drug sildenafil may benefit patients with Leigh syndrome, and particularly those carrying mutations in the mitochondrial gene MT-ATP6.
A new preprint article has been presented by an international team of researchers and clinicians led by members of the SIMPATHIC consortium Prof. Markus Schuelke and Prof. Alessandro Prigione.
In this work, entitled “Pluripotent stem cell-based drug discovery uncovers sildenafil as a treatment for mitochondrial disease”, the scientists provide some first evidence that the drug sildenafil may benefit patients with Leigh syndrome, and particularly those carrying mutations in the mitochondrial gene MT-ATP6. The evidence comes from studies in cells cultured in the laboratory and a small group of 6 patients treated with the drug. An official clinical trial is needed to confirm these findings. This publication is a preprint and still needs to be reviewed by peers in the field.
IMP is excited to be part of this project and the potential life-changing impact it may have on people with Leigh syndrome. However, it is vital to only use sildenafil with clinical supervision. Information about the clinical trial can be found below with more becoming available over the coming months.
For patients:
We strongly advise against taking the sildenafil drug without clinical supervision due to its safety risks. We recommend always following the advice of your responsible clinicians. A randomized clinical trial with sildenafil in Leigh syndrome patients with MT-ATP6 mutations is scheduled for 2016.
Patients interested in participating in this trial are advised to follow the communications of the SIMPATHIC consortium (www.simpathic.eu) which is acting in collaboration with International Mito Patient (IMP). We will soon provide more information regarding the details of the trial and related European recruitment centers. Patients who have already taken sildenafil prior the trial cannot be included.
More information on Leigh syndrome and the results presented in the preprint
Leigh syndrome is a severe mitochondrial disease that affects tissues with high energy needs such as the brain and the muscles, leading to motor and developmental delays. The disease typically worsens after metabolic crises due to sudden increased energy requirement during infections or states of stress. The most frequently affected gene in Leigh syndrome is MT-ATP6, which islocated on the mitochondrial DNA and encoding a component of the ATP synthase responsible for the generation of ATP, which is the energy currency of the cells.
In recent years, several therapies for Leigh syndrome have been proposed. However, very few have been tested in patients, and none have been found beneficial in clinical settings. Therefore, there are currently no disease-modifying treatments available for patients with Leigh syndrome. A major obstacle to identifying effective treatments is the lack of cellular and animal models of mitochondrial gene defects because of the difficulty of mitochondrial gene editing.
In this preprint, the scientists conducted a large drug discovery screen driven by Leigh syndrome patient-derived induced pluripotent stem cells (iPSCs). They investigated a library of potentially repurposable compounds and identified the group of phosphodiesterase 5 (PDE5) inhibitors as lead substances. Later, they focused on the PDE5 inhibitor sildenafil, given its well-known safety-efficacy profile for long term use in children and adults with pulmonary hypertension.
In addition to preclinical studies, the scientists report the clinical findings in six patients with Leigh syndrome carrying different MT-APT6 mutations treated with sildenafil as chronic off-label compassionate treatment. These preliminary results of the open-label study are encouraging and indicate some improvement in clinical symptoms related to motor ability and overall quality of life, although safety and efficacy still need to be determined using a rigorous study design including blinding, randomization, and placebo.
The work shown in the preprint was supported by several national and international funds including the European Commission’s Horizon Europe Programme (SIMPATHIC consortium), the European Joint Programme for Rare Diseases (EJPRD) (CureMILS consortium). Additional support was provided by several patient organizations and foundations including Mitocon, Cure Mito, Cure ATP6, UMDF, PALS, Mito Help, and Mito Foundation. The work has been conducted in collaboration with International Mito Patients (IMP) who is an official member of the consortium CureMILS and the consortium SIMPATHIC.
The next step is now to determine how effective sildenafil is in children and adults with Leigh syndrome using a formal randomized controlled clinical trial. To reach this goal, the scientists are seeking scientific advice from the European Medicines Agency (EMA) and were granted an Orphan Drug Designation (ODD) to the use of sildenafil for the treatment of Leigh syndrome (EU/3/23/2831).
SIMPATHIC will now build on these exciting findings to establish a European multi-national clinical trial for patients with Leigh syndrome carrying MT-ATP6 mutations.
The goal of this trial will be:
- To understand the safety of sildenafil in the Leigh syndrome patient population. In determining the doses effective in treating pulmonary hypertension, high doses of sildenafil were found to lead to increased side effects and mortality rates.
Therefore, there are potentially high risks associated with this treatment when not carefully administered. These safety concerns will be addressed in the trial by selecting dosages which we expect to be safe based on expertise and simulation studies, and by closely monitoring safety profiles and adverse events.
- To address the potential efficacy of sildenafil in patients with Leigh syndrome carrying MT-ATP6 mutations. This trial will be designed with the aim to obtain a registered license for the use of the drug for treatment of this patient population, so that the therapy can be reimbursed by national health insurers. To reach this goal, we are open to partnering with a Marketing Authorization Holder (MAH) for sildenafil.
We expect to start enrolling patients in early 2026. We will provide additional details with respect to eligibility criteria and European trial centers in the coming months.
To clinical colleagues: Please keep us informed of patients that may be interested in participating in this trial. Since Leigh syndrome is a rare disease, we would urge not to start additional compassionate treatments in order to be able to systematically investigate efficacy and safety and to enable a sufficient number of patients to participate in the trial.
If you are still considering starting a compassionate treatment with sildenafil, we would be very grateful if you could please let us know and keep us informed on the outcomes. We will be happy to offer to coordinate data collection, using a standardised protocol with predefined outcome measures. In this way, we would be able to gain additional insights into the effects of this potential therapy.
For any questions, please contact: Simpathic.aig@radboudumc.nl