Accurate prediction of protein stability upon a point mutation has important applications in drug discovery and personalized medicine. It remains a challenging issue in computational biology. Existing computational prediction methods, which range from mechanistic to supervised learning approaches, have experienced limited progress over the last few decades. This stagnation is largely due to their heavy reliance on both the quantity and quality of the training data. This is evident in recent state-of-the-art methods that continue to yield substantial errors on two challenging blind test sets: frataxin and p53, with average root-mean-square errors exceeding 3 and 1.5 kcal/mol, respectively, which is still above the theoretical 1 kcal/mol prediction barrier. Rigorous approaches, on the other hand, offer greater potential for accuracy without relying on training data but are computationally demanding and require both wild-type and mutant structure information. Although they showed high accuracy for conserving mutations, their performance is still limited for charge-changing mutation cases. This might be due to the lack of an available mutant structure, often represented by a simplified capped peptide. The recent advances in protein structure prediction methods now make it possible to obtain structures comparable to experimental ones, including complete mutant structure information. In this work, the authors compare the performance of supervised learning-based methods and rigorous approaches for predicting protein stability on point mutations in difficult targets: frataxin and p53. The rigorous alchemical method significantly surpasses state-of-the-art techniques in terms of both the root-mean-squared error and Pearson correlation coefficient in these two challenging blind test sets. Additionally, the authors propose an improved alchemical method that employs the pmx double-system/single-box approach to accurately predict the folding free energy change upon both conserving and charge-changing mutations. The enhanced protocol can accurately predict both types of mutations, thereby outperforming existing state-of-the-art methods in overall performance.
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Scientific News
FARA funds research progress
In this section, you will find the most recent FA research publications, many of which are funded by FARA, as well as information on upcoming conferences and symposiums. You can search for articles by date using the archive box in the right hand column. To locate FARA Funded or Supported Research, click the hyperlink in the right hand column. You may also search for specific content using key words or phrases in the search button at the top right of your screen. Please be sure to visit other key research sections of our website for information on FARA's Grant Program and the Treatment Pipeline.
Comparing Supervised Learning and Rigorous Approach for Predicting Protein Stability upon Point Mutations in Difficult Targets
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New Grant Awarded to Shannon Boye, PhD – Can we prevent vision loss in FA with gene therapy?
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Can we prevent vision loss in FA with gene therapy?
Vision loss in Friedreich’s ataxia (FA) is often an under-appreciated symptom, but it can significantly impact quality of life. Vision loss can be largely attributed to degeneration of a special cell type in the retina of the eye called the Retinal Gangion Cell (RGC).
We are pleased to award a grant to Dr. Shannon Boye at the University of Florida. Dr. Boye’s lab has developed a mouse model of vision loss in FA by knocking out frataxin expression in RGCs. Her lab will work to develop an AAV-gene therapy that delivers frataxin to the eye via a direct injection. They will test the ability of this gene therapy to prevent vision loss in their FA mouse model. They will also use the mouse model data to optimize the gene therapy for safety and efficiency. In addition to gene therapy, this mouse model has the potential to be useful in the development of other therapies that address vision loss in FA.
New Grant Awarded to Mark Payne, MD – Could a potential treatment for Duchenne Muscular Dystrophy (DMD) also treat the cardiac disease in Friedreich's ataxia (FA)?
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Could a potential treatment for Duchenne Muscular Dystrophy (DMD) also treat the cardiac disease in Friedreich's ataxia (FA)?
FA can often give rise to cardiac complications and a reduction in heart function. When the heart has severe fibrosis (scar tissue), cardiac function decreases, leading to heart failure and early death.
In patients with DMD, the heart also develops fibrosis. An investigational drug called Ifetroban has been shown to improve cardiac function and increase lifespan in DMD mice. Ifetroban is currently in clinical trials for DMD.
We are pleased to award a grant to Dr. Mark Payne at Indiana University School of Medicine to study the potential use of Ifetroban in FA. Dr. Payne’s lab will first test whether Ifetroban decreases fibrosis in the hearts of an FA mouse model. They will then test whether Ifetroban increases the lifespan of these mice.
This work will study the mechanism of fibrosis in the FA heart and test a potential treatment for it. If successful, this will provide the preliminary data needed to support a clinical trial in humans with FA-related cardiac disease.
Co-sponsor: fara Australia
New Grant Awarded to Stephanie Cherqui, PhD – Can immune cells of the brain be used to rescue neurons in FA?
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Can immune cells of the brain be used to rescue neurons in FA?
Dr. Stephanie Cherqui at the University of California, San Diego, has previously shown that gene editing of stem cells could be done outside of the body to repair the frataxin gene. Transplanting these edited cells into the body corrected some of the complications of Friedreich’s ataxia (FA) in a mouse model.
She hypothesized that these edited stem cells differentiated into brain immune cells (microglia) and that the improvement of the mice was due to both the repair of the microglia and the transfer of frataxin from the healthy microglia into diseased neurons.
We are pleased to award a grant to Dr. Cherqui to continue this work by investigating how microglia contribute to FA and whether gene editing of stem cells can help treat the disease.
This work will advance our understanding of microglia-neuron interactions and provide supporting evidence for the development of gene-edited stem cells as a potential treatment for FA!
Proprioceptive and tactile processing in individuals with Friedreich ataxia: an fMRI study
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The impact of the somatosensory system on ataxic symptoms in Friedreich ataxia (FA) remains debated. This study aims to better evaluate the contribution of somatosensory processing to ataxia clinical severity by simultaneously investigating passive movement and tactile pneumatic stimulation in individuals with FA. Twenty patients with FA and 20 healthy participants were included. All subjects underwent two 6 min block-design functional magnetic resonance imaging (fMRI) paradigms consisting of twelve 30 s alternating blocks (10 brain volumes per block, 120 brain volumes per paradigm) of a tactile oddball paradigm and a passive movement paradigm. Spearman rank correlation tests were used for correlations between BOLD levels and ataxia severity. The passive movement paradigm led to the lower activation of primary (cSI) and secondary somatosensory cortices (cSII) in FA compared with healthy subjects (respectively 1.1 ± 0.78 vs. 0.61 ± 1.02, p = 0.04, and 0.69 ± 0.5 vs. 0.3 ± 0.41, p = 0.005). In the tactile paradigm, there was no significant difference between cSI and cSII activation levels in healthy controls and FA (respectively 0.88 ± 0.73 vs. 1.14 ± 0.99, p = 0.33, and 0.54 ± 0.37 vs. 0.55 ± 0.54, p = 0.93). Correlation analysis showed a significant correlation between cSI activation levels in the tactile paradigm and the clinical severity (R = 0.481, p = 0.032). This study captured the difference between tactile and proprioceptive impairments in FA using somatosensory fMRI paradigms. The lack of correlation between the proprioceptive paradigm and ataxia clinical parameters supports a low contribution of afferent ataxia to FA clinical severity.
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- Disease Delineation for Multiple Sclerosis, Friedreich Ataxia, and Healthy Controls Using Supervised Machine Learning on Speech Acoustics
- The therapeutic potential of targeting ferroptosis in the treatment of mitochondrial cardiomyopathies and heart failure
- Rationale and protocol of a double-blind, randomized, placebo-controlled trial to test the efficacy, safety, and tolerability of dimethyl fumarate in Friedreich Ataxia (DMF-FA-201)
- Patient-derived iPSC models of Friedreich ataxia: a new frontier for understanding disease mechanisms and therapeutic application
- Neurologic orphan diseases: Emerging innovations and role for genetic treatments