A “Leap-of-Faith” approach is used to treat patients with previously unknown ultrarare pathogenic mutations, often based on evidence from patients having dissimilar but more prevalent mutations. This uncertainty reflects the need to develop personalized prescreening platforms for these patients to assess drug efficacy before considering clinical trial enrollment. In this study, we report an 18-year-old ECHS1 patient with Leigh-like syndrome. This patient had previously participated in two clinical trials with unfavorable responses. We established an induced pluripotent stem cell (iPSC)–based platform for this patient, and assessed the efficacy of a panel of drugs. The iPSC platform validated the safety and efficacy of the screened drugs. The efficacy of three of the screened drugs was also investigated in the patient. After 3 years of treatment, the drugs were effective in shifting the metabolic profile of this patient toward healthy control. Therefore, this personalized iPSC-based platform can act as a prescreening tool to help in decision-making with respect to patient’s participation in future clinical trials.
An iPSC-based personalized prescreening tool helps in selection of suitable clinical trial for patients with ultrarare diseases.
In the case of inborn errors of metabolism, patients with previously unknown ultrarare variants differ with respect to underlying disease pathophysiology and mechanism of disease progression. This creates a group of patients predicted to have an uncertain response to a drug in a clinical trial, because the enrollment criteria for these clinical trials are mostly established through evaluation of patients with similar phenotypes but different mutations (1). This leads to delayed or imprecise treatment options for patients with ultrarare novel variants. Here, we report this 18-year-old patient with Leigh-like syndrome (LS-like) with compound heterozygous variants in the ECHS1 gene. One of the variants in this patient is novel, but there is a lack of information on both variants observed here. There is thus the scenario where new drug administration and clinical trial enrollment for this patient are fraught with uncertainty. Furthermore, drug trials need to be carried out sequentially and enough time needs to elapse between experimental drug testing periods for washout and recovery. This is problematic, where time is of the essence in the search for a possible effective treatment for hereditary metabolic disorders with still no effective treatment options. This “trial and error” approach is still ongoing for this patient. Two such attempts have been met with unfavorable responses: (i) α-tocopherol (Toco) was discontinued as the patient reported discomfort and (ii) the patient had participated in a clinical trial [RP103-MITO-001(NCT02023866)] involving cysteamine (Cys) salt but withdrew due to side effects. Therefore, a personalized prescreening tool that could help decide whether enrollment in a particular clinical trial with the assurance of best possible drug safety and efficacy would benefit this individual (and similarly other patients) with novel ultrarare mutations.
Induced pluripotent stem cells (iPSCs) have recently gained preeminence in disease modeling by recapitulating identical genetic and phenotypic aberrations (2), allowing demonstration of personalized medicine. Several single organ–specific disorders like Long-QT syndrome and Parkinson’s disease have been rigorously modeled through iPSC, providing better understanding of disease progression and drug efficacy testing platforms (3). Likewise, human iPSC–derived cardiomyocytes (CMs) have already been approved by the Food and Drug Administration (FDA) for safety and efficacy evaluations of new drugs (4). In the current study, we have demonstrated the development of an iPSC-based stable multisystem clinical trial selection platform for the patient with LS-like syndrome. We compared the LS-like patient with negative controls (healthy individuals) and a positive control (patient with classic LS). Leigh/Leigh-like syndrome (LS) is a rare group of progressive mitochondrial disorders of oxidative phosphorylation that involves multisystem abnormalities and heterogeneous manifestations. More than 100 mutations in mitochondrial and genetic DNA have been reported in LS, with novel variants being found regularly (5). With treatment options lacking, patients and physicians often explore experimental opportunities through enrollment in clinical trials or by sifting through the results of completed ones (6). However, the heterogeneity of mutations within patients with LS puts them at a risk of adverse drug response and uncertain clinical response. With scarcity of conventional models (cellular or animal), there is a wide preclinical to clinical gap to finding an optimal treatment for these patients.
The platform demonstrated here included iPSC-derived fibroblasts (representation of general cell population in the body), neural progenitor cells (NPCs) and mature neurons (neural system is the primary organ affected in many LS cases), and CMs (cardiac involvement is reported to lesser degree). Thereafter, this multisystem platform was used to assess the toxicity and efficacy of a panel of seven drugs (in clinical application or being tested in ongoing clinical trials) in affected iPSC-derived cells.
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