Clinical trials in mitochondrial disorders, an update

Almannai, Mohammed; El‐Hattab, Ayman W.; Ali, M. Nadir; Soler‐Alfonso, Claudia; Scaglia, Fernando

doi:10.1016/j.ymgme.2020.10.002

Cited by 50 publications

(40 citation statements)

References 155 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Strategies to improve mitochondrial function have been under consideration for the treatment of neurological and psychiatric disorders for quite some time, with limited success in clinical trials [ 271 , 272 , 273 , 274 , 275 ], despite promising results in animal models [ 276 , 277 , 278 , 279 , 280 , 281 ]. Even in individuals with genetic mutations that cause mitochondrial dysfunction and multi-organ disease, there are few treatment options [ 282 ]. PGC-1α was initially viewed as an ideal candidate to provide a full transcriptional program for enhancing citric acid cycle flux and oxidative phosphorylation capacity in parallel with the upregulation of genes involved in antioxidant defense.…”

Section: Viable Avenues For Drug Discovery and Therapeutic Intervementioning

confidence: 99%

Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities

McMeekin

Fox

Boas

et al. 2021

Cells

View full text Add to dashboard Cite

Substantial evidence indicates that mitochondrial impairment contributes to neuronal dysfunction and vulnerability in disease states, leading investigators to propose that the enhancement of mitochondrial function should be considered a strategy for neuroprotection. However, multiple attempts to improve mitochondrial function have failed to impact disease progression, suggesting that the biology underlying the normal regulation of mitochondrial pathways in neurons, and its dysfunction in disease, is more complex than initially thought. Here, we present the proteins and associated pathways involved in the transcriptional regulation of nuclear-encoded genes for mitochondrial function, with a focus on the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α). We highlight PGC-1α’s roles in neuronal and non-neuronal cell types and discuss evidence for the dysregulation of PGC-1α-dependent pathways in Huntington’s Disease, Parkinson’s Disease, and developmental disorders, emphasizing the relationship between disease-specific cellular vulnerability and cell-type-specific patterns of PGC-1α expression. Finally, we discuss the challenges inherent to therapeutic targeting of PGC-1α-related transcriptional programs, considering the roles for neuron-enriched transcriptional coactivators in co-regulating mitochondrial and synaptic genes. This information will provide novel insights into the unique aspects of transcriptional regulation of mitochondrial function in neurons and the opportunities for therapeutic targeting of transcriptional pathways for neuroprotection.

show abstract

Section: Viable Avenues For Drug Discovery and Therapeutic Intervementioning

confidence: 99%

Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities

McMeekin

Fox

Boas

et al. 2021

Cells

View full text Add to dashboard Cite

show abstract

“…Although the function and activity of PINK1 and its downstream substrates are not fully elucidated, it is clear that PINK1 kinase plays key roles in maintaining mitochondrial function and cellular homeostasis in addition to regulating mitophagy. Recently, there is an increasing number of clinical trials with various therapeutic modalities by targeting different aspects of mitochondrial dysfunction, which include modulation of oxidative stress, augmentation of mitochondrial biogenesis, and stimulating mitochondrial dynamics [ 88 , 89 ]. Given the diverse roles of PINK1 in mitochondria, future studies to determine the association between PINK1 and the approved/ongoing clinical trial drugs such as Sonlicromanol (KH176), Bezafibrate, and NAD + precursors/modulators deserve further exploration [ 88 , 89 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, there is an increasing number of clinical trials with various therapeutic modalities by targeting different aspects of mitochondrial dysfunction, which include modulation of oxidative stress, augmentation of mitochondrial biogenesis, and stimulating mitochondrial dynamics [ 88 , 89 ]. Given the diverse roles of PINK1 in mitochondria, future studies to determine the association between PINK1 and the approved/ongoing clinical trial drugs such as Sonlicromanol (KH176), Bezafibrate, and NAD + precursors/modulators deserve further exploration [ 88 , 89 ]. These studies will not only provide a deeper understanding of the molecular mechanism of the drugs but also identify novel PINK1-targeted agents for future clinical application.…”

Section: Discussionmentioning

confidence: 99%

The Mitochondrial Kinase PINK1 in Diabetic Kidney Disease

Huang

Bian

Cao

et al. 2021

IJMS

View full text Add to dashboard Cite

Mitochondria are critical organelles that play a key role in cellular metabolism, survival, and homeostasis. Mitochondrial dysfunction has been implicated in the pathogenesis of diabetic kidney disease. The function of mitochondria is critically regulated by several mitochondrial protein kinases, including the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1). The focus of PINK1 research has been centered on neuronal diseases. Recent studies have revealed a close link between PINK1 and many other diseases including kidney diseases. This review will provide a concise summary of PINK1 and its regulation of mitochondrial function in health and disease. The physiological role of PINK1 in the major cells involved in diabetic kidney disease including proximal tubular cells and podocytes will also be summarized. Collectively, these studies suggested that targeting PINK1 may offer a promising alternative for the treatment of diabetic kidney disease.

show abstract

“…Most interventions and guidelines are related to symptomatic treatment, with supplementation of cofactors, vitamins, or antioxidants, and mild exercises are recommended. Despite numerous studies, the efficacy of most of these interventions has not been confirmed [ 39 , 40 , 41 , 42 , 43 ].…”

Section: Pharmacological Treatment Of Epilepsy In Patients With Mitochondrial Diseasementioning

confidence: 99%

Epilepsy in Mitochondrial Diseases—Current State of Knowledge on Aetiology and Treatment

2021

View full text Add to dashboard Cite

Mitochondrial diseases are a heterogeneous group of diseases resulting from energy deficit and reduced adenosine triphosphate (ATP) production due to impaired oxidative phosphorylation. The manifestation of mitochondrial disease is usually multi-organ. Epilepsy is one of the most common manifestations of diseases resulting from mitochondrial dysfunction, especially in children. The onset of epilepsy is associated with poor prognosis, while its treatment is very challenging, which further adversely affects the course of these disorders. Fortunately, our knowledge of mitochondrial diseases is still growing, which gives hope for patients to improve their condition in the future. The paper presents the pathophysiology, clinical picture and treatment options for epilepsy in patients with mitochondrial disease.

show abstract

Clinical trials in mitochondrial disorders, an update

Cited by 50 publications

References 155 publications

Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities

Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities

The Mitochondrial Kinase PINK1 in Diabetic Kidney Disease

Epilepsy in Mitochondrial Diseases—Current State of Knowledge on Aetiology and Treatment

Contact Info

Product

Resources

About