Gene Silencing Therapies

Gene silencing therapies work by reducing the levels of abnormal huntingtin (HTT) protein that is produced in patients with Huntington’s disease.

How are proteins made in cells?

All instructions that are used to make proteins are contained in the DNA. Molecules known as ribonucleic acids (RNA) form a copy of these instructions, which are then read by ribosomes, the protein-making machinery of the cells, to make the protein of interest.

People with Huntington’s disease have a mutation in the HTT gene, which leads to the production of defective HTT (or huntingtin) protein. This causes damage to brain cells.

Types of gene silencing therapies

Gene-silencing therapies that are currently being investigated in Huntington’s disease work in a few different ways. Antisense oligonucleotides (ASOs) and RNA-interference (RNAi)-based therapies work by binding specifically to faulty RNA sequences that are made from mutated HTT gene codes.

The CRISPR/CAS9 system, on the other hand, aims to directly modify the mutated HTT gene.

Antisense oligonucleotides

An antisense oligonucleotide currently under clinical investigation for Huntington’s disease is the investigative IONIS-HTTRx molecule (also called RG6042). It works by binding to and marking HTT mRNA for destruction. IONIS-HTTRx was initially developed by Ionis Pharmaceuticals and is now licensed to Roche.

Recent Phase 1/2a clinical trial results (NCT02519036) indicate this therapy may be successful in decreasing levels of abnormal HTT protein. An open-label extension trial (NCT03342053) to assess the long-term safety and efficacy of this compound is currently ongoing.

Wave Life Sciences is also in the midst of producing two investigative antisense oligonucleotides, WVE-120101 and WVE-120102. Both compounds are currently being investigated in Phase 1/2  clinical trials.

RNAi-based therapies

RNAi-based therapies differ from antisense oligonucleotides in that RNAi-compounds are usually delivered inside cells using a carrier, normally an inactivated virus. While ASOs are meant to bind directly to the specific mutated RNA sequence, RNAi-based compounds are first incorporated into naturally-occurring gene-silencing proteins present in the body before being able to target the mutated RNA sequence.

Generally, the choice between ASOs or RNAi-based compounds depends on the location of cells that require gene silencing as well as on the type of disease.

An RNAi-based therapy candidate called AMT-130 by uniQure is currently in preclinical stages of development. AMT-130 is carried inside nerve cells by a noninfectious adeno-associated virus. It then binds to and marks mutated HTT RNAs for degradation.

VY-HTT01 is another RNAi-based investigative therapy. It is being developed by Voyager Therapeutics in collaboration with Sanofi-Genzyme and the CHDI Foundation.

CRISPR/Cas9 system

The CRISPR/Cas9 system is the latest in gene-silencing and altering technology. Discovered in 2015, it has been applied successfully in animal studies of several single-gene mutation disorders such as sickle cell anemia, hemophilia, and cystic fibrosis.

CRISPR/Cas9 works by “cutting out” specific gene sequences in the DNA. The cell’s repair mechanism then reattaches the cut ends. This may be particularly useful in the case of Huntington’s disease, as the gene defect causing the disease is a CAG repeat expansion, which means there are too many CAG repeats in patients’ DNA.

Scientists have successfully used CRISPR/Cas9 to cut out CAG repeats in animal models of Huntington’s disease, with the animals demonstrating improved motor symptoms.

Several animal studies have also shown that the CRISPR/Cas9 system is able to effectively remove the mutated HTT gene sequence without adversely affecting the rest of the DNA.

The CRISPR/Cas9 system has the advantage of being cheaper and more accurate and effective compared to other gene-editing systems. But it has yet to be tested in clinical trials, and some scientists have concerns about its safety and gene editing ethical issues.


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