Back to theodicy: fixing genome mistakes (The nature of a \'Creator\')

by David Turell @, Friday, August 06, 2021, 14:58 (77 days ago) @ David Turell

A new approach to fixing a genetic mistake, phenylketonuria, handled now by special diets:

https://science.sciencemag.org/content/373/6555/623

"Over the past several years, advances in RNA sequencing have led to an increased appreciation of the prevalence and function of noncoding RNAs, including long noncoding RNAs (lncRNAs). These are typically expressed in a tissue-specific manner in healthy tissues and are often dysregulated in disease, making them potential biomarkers and therapeutic targets. On page 662 of this issue, Li et al. reveal the biological importance of a lncRNA in an inherited metabolic disorder called phenylketonuria (PKU) and demonstrate in mice that a molecule that mimics the functional region of this lncRNA is a promising therapeutic. This discovery suggests that short lncRNA fragments could overcome some of the challenges faced by other RNA therapeutic modalities.

"RNA-based and RNA-targeting therapeutics have many advantages: They are cost-effective, are relatively simple to manufacture, can target otherwise undruggable pathways, and have demonstrated success in the treatment of several diseases. Although RNA therapeutics have a long and bumpy history, advances in the generation, purification, and cellular delivery of short oligonucleotides and long RNAs have led to regulatory approval of several RNA-focused therapies, including the much-celebrated messenger RNA (mRNA)–based COVID-19 vaccines.

"The human genome encodes a large number of RNA molecules that do not encode functional proteins, including tens of thousands that are classified as lncRNAs. lncRNAs and mRNAs are virtually identical at the molecular level, although lncRNA production is typically much more tissue specific. Also, lncRNA genes evolve much faster than protein-coding ones. lncRNAs have diverse roles, including in gene regulation and as scaffolds for macromolecular assemblies. Some lncRNAs function in cis—that is, in the vicinity of their site of transcription—whereas others are trans-acting, and their function is not affected by their production site within the genome. Because lncRNAs are expressed in a cell-, tissue-, developmental stage–, or disease-specific manner, their modulation could have substantial, but focal, consequences, which are expected to be well tolerated. However, the progress in elucidating their functions and causally linking genetic changes in lncRNA loci to disease has been slow.

"Antisense oligonucleotides (ASOs) are currently the most common approach for therapeutic targeting of RNAs. These are single-stranded oligonucleotides that base pair with a target RNA and can either lead to target degradation or alter target RNA structure and/or its ability to interact with other factors. Chemical modifications of ASOs make them highly stable and able to permeate cells, and considerable progress has been made in the improvement of their pharmacological properties, allowing development of effective therapeutics such as nusinersen for spinal muscular atrophy

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"Several hurdles still need to be overcome before lncRNAs or fragments thereof realize their full therapeutic potential. Perhaps most important is the need for advances in the methods to deliver RNA molecules to specific tissues and cell types (as nanoparticles or through other vehicles), which will also benefit therapeutic mRNAs and ASOs (6). The repertoire of lncRNAs whose biology is properly understood and linked to specific pathological states also needs to be expanded."

Comment: Humans are slowly learning to edit genome metabolic errors. The complexity of the genome is mind-boggling, showing us a designer is required


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