RNA Treatments

Batten disease (also known as neuronal ceroid lipofuscinosis, or NCL) refers to a group of genetic, neurological conditions in which there is an abnormal accumulation of lipofuscins (fat and protein containing pigments) inside cells. This substance is particularly toxic to nerve cells, which is why neurological symptoms such as seizures, blindness, motor, and cognitive decline are frequently observed in people with Batten disease.

Ribonucleic acid (RNA) modulators are a relatively new type of treatment that is aimed at overcoming the effects of errors in the DNA by influencing how RNAs are read and carry out the instructions contained in the DNA.

RNA modulators have not yet entered clinical trials for Batten disease and are still in pre-clinical stages of development.

How proteins are made in the cell

RNAs are the main information-carrying molecules that allow cells to make proteins based on the information contained in the DNA. In other words, they are intermediate molecules that link the instructions contained in the DNA with the final protein product. They are like photocopies of parts of DNA that leave the cell nucleus and can be read by the protein-making machinery of the cell known as ribosomes.

How RNA modulators work

Different types of Batten disease are caused by different gene defects that result in cells being unable to clear lipofuscins. Although it is not fully understood how these mutations cause the symptoms of the disease, scientists have discovered they cause abnormalities in enzymes or proteins involved in lipofuscin processing.

DNA mutations result in defective RNAs, which go on to cause these protein/enzyme abnormalities. RNA modulators work by modifying problematic RNAs, thus ensuring that either non-functioning proteins or enzymes are not produced, or the correct ones are.

RNA modulators available are nonsense suppression therapy and antisense oligonucleotides.

Nonsense suppression therapy

Some forms of Batten disease are caused by mutations known as nonsense mutations in the DNA. These mutations result in a premature stop signal in the RNA. Ribosomes “reading” these faulty signals stop making the corresponding protein when they come across this signal, inadvertently producing unfinished proteins that do not function properly.

Nonsense suppression therapy works by allowing ribosomes to ignore the nonsense mutation-induced stop signal, prompting ribosomes to continue reading through the entire set of protein instructions. This way, full-length proteins that work properly can be produced.

PTC-124, also known as ataluren, manufactured by PTC Therapeutics is a nonsense suppression therapy that is currently being developed for Duchenne muscular dystrophy and cystic fibrosis.

A study done on cells taken from patients with infantile Batten disease who had nonsense mutations in the PPT1 gene found that PTC-124 was able to increase PPT1 enzyme levels. Similar effects also were observed in proof-of-principle studies on mice with nonsense mutations in the PPT1 gene. However, PTC Therapeutics has not yet indicated that it has plans to continue developing PTC124 for Batten disease.

Antisense oligonucleotides

mRNA sequences, such as the defective ones found in Batten’s disease, are very specific. Antisense oligonucleotides are small compounds that are designed to bind only to certain RNA sequences. Once bound, these compounds are able to modify the faulty mRNA by either stopping it from being read by the ribosomes, or by promoting its breakdown in the cell. Ultimately, antisense oligonucleotides aim to stop the production of the defective proteins.

Sanford Research in South Dakota, in collaboration with Rosalind Franklin University in Chicago, Illinois, designed antisense oligonucleotides that potentially may treat Batten disease caused by mutations in the PPT1, TPP1, CLN3, and CLN6 genes, although there have been no studies published.

Antisense oligonucleotides also are being developed for other conditions such as spinal muscular atrophy (SMA), Duchenne muscular dystrophy, Usher syndrome, and Niemann-Pick Disease Type C.


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