Day: March 17, 2023

A Genetic Treatment for ALS That Restores Key Protein May Be Possible

DNA repair
Source: Pixabay/CC0

In virtually all persons with amyotrophic lateral sclerosis (ALS) and in up to half of all cases of Alzheimer’s disease (AD) and frontotemporal dementia, a protein called TDP-43 is lost from its normal location in the nucleus of the cell. In turn, this triggers the loss of stathmin-2, a protein crucial to regeneration of neurons and the maintenance of their connections to muscle fibres.

Writing in Science, a team of scientists demonstrate that stathmin-2 loss can be rescued using designer DNA drugs that restore normal processing of protein-encoding RNA.

“With mouse models we engineered to misprocess their stathmin-2 encoding RNAs, like in these human diseases, we show that administration of one of these designer DNA drugs into the fluid that surrounds the brain and spinal cord restores normal stathmin-2 levels throughout the nervous system,” said senior study author Don Cleveland, PhD, Distinguished Professor of Medicine, Neurosciences and Cellular and Molecular Medicine at University of California San Diego School of Medicine.

Cleveland is broadly credited with developing the concept of designer DNA drugs, which act to either turn on or turn off genes associated with many degenerative diseases of the aging human nervous system, including ALS, AD, Huntington’s disease and cancer.

Several designer DNA drugs are currently in clinical trials for multiple diseases. One such drug has been approved to treat a childhood neurodegenerative disease called spinal muscular atrophy.

The new study builds upon ongoing research by Cleveland and others regarding the role and loss of TDP-43, a protein associated with ALS, AD and other neurodegenerative disorders. In ALS, TDP-43 loss impacts the motor neurons that innervate and trigger contraction of skeletal muscles, causing them to degenerate, eventually resulting in paralysis.

“In almost all of instances of ALS, there is aggregation of TDP-43, a protein that functions in maturation of the RNA intermediates that encode many proteins. Reduced TDP-43 activity causes misassembly of the RNA-encoding stathmin-2, a protein required for maintenance of the connection of motor neurons to muscle,” said Cleveland.

“Without stathmin-2, motor neurons disconnect from muscle, driving paralysis that is characteristic of ALS. What we have now found is that we can mimic TDP-43 function with a designer DNA drug, thereby restoring correct stathmin-2 RNA and protein level in the mammalian nervous system.”

Specifically, the researchers edited genes in mice to contain human STMN2 gene sequences and then injected antisense oligonucleotides – small DNA or RNA pieces that can bind to specific RNA molecules, blocking their ability to make a protein or changing how their final RNAs are assembled – into cerebral spinal fluid. The injections corrected STMN2 pre-mRNA misprocessing and restored stathmin-2 protein expression fully independent of TDP-43 function.

“Our findings lay the foundation for a clinical trial to delay paralysis in ALS by maintaining stathmin-2 protein levels in patients using our designer DNA drug,” Cleveland said.

Source: University of California – San Diego

WHO Updates SARS-CoV-2 Definitions to Reflect Omicron Dominance

Source: Pixabay CC0

The World Health Organization (WHO) announced that it has updated its tracking system and working definitions for variants of SARS-CoV-2, to better reflect the current global variant landscape, to independently evaluate Omicron sublineages in circulation, and classify new variants more clearly when required.

Omicron variants now accounts for 98% of circulating SARS-CoV-2, and new variants will likely emerge from this genetic background. Based on its latest risk assessment [PDF], South Africa has reported a strong increase in XBB.1.5 from 1% in December 2022, to 10% in January 2023, and 76% as of the latest report from February 2023.

Based on comparisons of antigenic cross reactivity using animal sera, replication studies in experimental models of the human respiratory tract, and evidence from clinical and epidemiological studies in humans, WHO experts conclude that, compared to previous variants, Omicron represents the most divergent variant of concern (VOC) seen so far. Since its emergence, Omicron viruses have continued to evolve genetically and antigenically with an expanding range of sublineages, which so far have had all been characterised by evasion of existing population immunity and a preference to infect the upper respiratory tract (versus lower respiratory tract), as compared to pre-Omicron VOCs.

The previous system classified all Omicron sublineages as part of the Omicron VOC and was not detailed enough to compare new descendent lineages with altered phenotypes to the Omicron parent lineages (BA.1, BA.2, BA.4/BA.5). So, WHO variant tracking system will consider the classification of Omicron sublineages independently as variants under monitoring (VUMs), variants of interest (VOIs), or VOCs.

WHO is also updating the working definitions for VOCs and VOIs. The main update consists in making the VOC definition more specific, to include major SARS-CoV-2 evolutionary steps that require major public health interventions.

In addition, going forward, WHO will assign Greek labels for VOCs, and will no longer do so for VOIs.

With these changes factored in, Alpha, Beta, Gamma, Delta as well as the Omicron parent lineage (B.1.1.529) are considered previously circulating VOCs. WHO has now classified XBB.1.5 as a VOI. 

WHO emphasizes that these changes do not imply that the circulation of Omicron viruses no longer pose a threat to public health. Rather, the changes have been made in order to better identify additional or new threats over and above those posed by the current Omicron viruses in circulation.

Study Reveals How Androgen Receptor Functions are Affected by Mutations

Testosterone molecule
Model of a testosterone molecule. Source: Wikimedia CC0

The androgen receptor is a key transcriptional factor for proper sex development, especially in males and the physiological balance of all the tissues that express this receptor. The androgen receptor is involved in several pathologies and syndromes, such as spinal and bulbar muscular atrophy or androgen insensitivity syndrome, for which there is no specific treatment. Regarded as the main initial and progression factor in prostate cancer, this receptor has been the main therapeutic target for the treatment against this disease for decades.

Now, a study published in Science Advances describes the structural and functional effects of mutations on the androgen receptor, as well as how these changes lead to the development of prostate cancer.

Point mutations in the androgen receptor

The human androgen receptor is a key protein in the development and functioning of the prostate in response to male hormones, such as testosterone. Point mutations in the androgen receptor – specifically, one amino acid swapped for another – are one of the main mechanisms than can lead to structural and functional alterations in the receptor, which result in the development of diseases.

The results of the University of Barcelona-led study show that the analysed mutations affect several functional regions of the union domain of the androgen receptor to testosterone. In particular, these are mutations that alter a region of the receptor which is the target for posttranscriptional modifications (that is, modifications in the protein once this is produced).

This type of chemical alterations affect specific amino acids of the androgen receptor and are executed by regulating proteins which are critical for the proper functioning of the receptor. If this receptor’s regulation pathway is altered, such as the case of the presence of mutations described by the team, its function is deregulated and it can be dysfunctional and cause pathologies.

“In our study, we experimentally checked that these mutations deregulate a specific mutation, known as arginine methylation, which is one of the posttranscriptional modifications, due to the structural changes these alterations produce in a functional area of the receptor. Also, we could observe that the deregulation of the androgen receptor methylation involves relevant changes in its function within the cell,” the team concludes.

Source: University of Barcelona

Strenuous Jobs Increase Men’s Cardiovascular Risk, but Reduce Women’s

Photo by K. Mitch Hodge on Unsplash

A long-term Danish study found that high physical activity at work was associated with higher risk of ischaemic heart disease (IHD) in men, but in women, this was associated with lower risk. The findings, published in the European Journal of Preventive Cardiology, highlight the importance of taking gender into account when considering the impact of high levels of occupational physical activity (OPA).

While previous studies have shown that physical activities in leisure time are protective against cardiovascular disease, high levels of OPA were shown to have no benefit – or even a detrimental effect.

The study followed up participants aged 30–61 years old after 34 years who took part in the Danish Monica 1 study in 1982–84. Participants, 1399 women and 1706 men, were actively employed, without prior IHD and who answered a question on OPA. The participants’ medical records were located in the Danish National Patient Registry and the researchers analysed the data, controlling for increasing numbers of factors such as age, then age and sex, and then age and sex plus factors such as smoking.

Compared to women doing sedentary work, women in all other OPA categories had a lower hazard ratio (HR) for IHD. Among men, the risk of IHD was 22% higher among those with light OPA, and 42% and 46% higher among those with moderate OPA with some lifting or strenuous work with heavy lifting, respectively, compared to men with sedentary OPA. Compared to women with sedentary work, HR for IHD was higher among men in all OPA categories, and a statistically significant interaction between OPA and sex was found.

Demanding or strenuous OPA seems to be a risk factor for IHD among men, whereas a higher level of OPA seems to protect from IHD among women. The researchers wrote that this underlines the importance of taking into account sex differences in studies of health effects of OPA. Future studies should investigate the underlying mechanisms for this difference, such as differences in exposure and physiology.

New Oral Psoriasis Drug a Step Closer After Successful Clinical Trials

Source: Danilo Alvesd on Unsplash

In a Phase 2b clinical trial, patients who took the peptide-based drug candidate JNJ-2113 had a 75% improvement in their plaque psoriasis compared to placebo, passing an important milestone in developing an oral treatment for the common skin disease. The drug is being developed by a company launched from The University of Queensland’s Institute for Molecular Bioscience (IMB) in collaboration with Janssen.

Protagonist Therapeutics was spun out of work by Associate Professor Mark Smythe to develop new drugs for conditions previously only treated with injectables. Dr Smythe said the trial result was a significant achievement for patients and the scientists involved.

“The trial has shown it’s possible to treat systemic diseases like psoriasis with peptide-based drugs that are orally delivered,” Dr Smythe said.

“Diseases such as psoriasis and inflammatory bowel disease have targets that previously could only be blocked by large molecules called macromolecular antibodies, which had to be injected because they’re too big to be taken in pills.

“The key to finding a molecule that worked but was small enough to be taken orally was seeing the animal venom research of my IMB colleagues.

“I realised that the constrained peptide molecules in venoms could both block the right targets and were small.”

Dr Smythe and his team developed techniques to stabilise the peptides enough so that they could be developed into an oral drug.

Protagonist was founded in 2001 with commercial support from UniQuest Pty Ltd, UQ’s commercialisation company.

Protagonist is based in the USA with an office in Brisbane and is one of 15 spin-out companies from IMB and one of 125 start-ups based on UQ intellectual property.

Source: The University of Queensland