A shot in the arm for HTT lowering: INSIGHTT trial begins testing SRP-1005

Another huntingtin (HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15) lowering drug has officially entered the clinic. The INSIGHTT study has begun dosing participants with SRP-1005, an experimental treatment developed by Sarepta Therapeuticstherapeutics treatments that aims to reduce production of the HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 protein.

There are already several different approaches to lowering HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 being tested in people. What sets SRP-1005 apart is how it is delivered. Rather than requiring brain surgery or delivery of a drug into the spinal fluid, SRP-1005 is given by an injection under the skin.

This trial is just beginning, so whether SRP-1005 will be safe or effective for people with Huntington’s disease (HD) remains to be seen. But getting another type of HTT-lowering technology into clinical testing gives the HD community another shot on goal and could help researchers learn how to make these treatments easier to deliver.

Same target, but a different way to get there

HD is caused by a change in the HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 gene, which contains the instructions for making the HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 protein. The expanded form of HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 is thought to drive many of the harmful changes that occur in HD, making lowering HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 an attractive therapeutic strategy.

Researchers are tackling this problem from several different angles. Some approaches use antisense oligonucleotidesASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene, or ASOsASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene, which are delivered into the spinal fluid. Others use gene therapy, which requires a one-time neurosurgical procedure to deliver genetic instructions directly into the brain. There are also oral HTT-lowering drugs, which are designed to alter how the HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 genetic message is processed.

SRP-1005 adds another technology to this growing toolbox: small interfering RNARNA the chemical, similar to DNA, that makes up the ‘message’ molecules that cells use as working copies of genes, when manufacturing proteins., or siRNAsiRNA A way of silencing genes using specially designed molecules of RNA – like DNA but made of only a single strand – that target the message molecules in cells and tell them not to make a certain protein. RNARNA the chemical, similar to DNA, that makes up the ‘message’ molecules that cells use as working copies of genes, when manufacturing proteins. might sound familiar to regular HDBuzz readers. The HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 gene is made of DNA, but cells first copy those genetic instructions into a temporary RNARNA the chemical, similar to DNA, that makes up the ‘message’ molecules that cells use as working copies of genes, when manufacturing proteins. message called messenger RNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein., or mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein.. That message is then used to make the HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 protein.

siRNAsiRNA A way of silencing genes using specially designed molecules of RNA – like DNA but made of only a single strand – that target the message molecules in cells and tell them not to make a certain protein molecules are designed to recognise particular RNARNA the chemical, similar to DNA, that makes up the ‘message’ molecules that cells use as working copies of genes, when manufacturing proteins. messages and trigger their destruction. SRP-1005 targets HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 mRNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein., with the aim of reducing the amount of HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 protein that cells produce.

Why this new delivery approach matters

One of the biggest challenges for drugs that target HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 RNARNA the chemical, similar to DNA, that makes up the ‘message’ molecules that cells use as working copies of genes, when manufacturing proteins. is getting them to the right place. The brain is protected by the blood-brain barrierblood-brain barrier A natural barrier, made from reinforcements to blood vessels, that prevents many chemicals from getting into the brain from the bloodstream, which is excellent at keeping potentially harmful substances out. But it’s also frustratingly good at keeping many potential medicines out too. This is one reason some experimental HD therapies have had to be administered directly into the spinal fluid or brain.

SRP-1005 is designed to tackle this problem differently. Sarepta is developing the drug to reach the brain following an injection into the tissue just beneath the skin, known as subcutaneous injection. SRP-1005 can hitch a ride across the blood-brain barrierblood-brain barrier A natural barrier, made from reinforcements to blood vessels, that prevents many chemicals from getting into the brain from the bloodstream by binding to a protein called the transferrin receptorReceptor a molecule on the surface of a cell that signalling chemicals attach to, which normally helps transport iron into the brain.

For now, another HTT-lowering strategy entering human testing means another opportunity to learn, and another shot on goal for the HD community

The INSIGHTT trial is therefore testing not only a new HTT-lowering molecule, but a potentially important new way of delivering this type of medicine.If this approach ultimately works, it could have practical implications for people with HD. A treatment given by this type of injection could potentially be less invasive and burdensome than repeated spinal injections or brain surgery.

There is an important distinction, though: this early trial still involves lumbar puncture procedures so researchers can measure SRP-1005 in cerebrospinal fluidCSF A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord. (CSFCSF A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord.). The potential promise here is therefore about how the treatment itself is delivered, rather than INSIGHTT being a procedure-free study. CSFCSF A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord. is still one of the best windows we have into brain health, HD-related changes, and any improvements in response to an experimental therapy.  

What will INSIGHTT tell us?

INSIGHTT is a small, first-in-human Phase 1 study. According to the current clinical trialclinical trial Very carefully planned experiments designed to answer specific questions about how a drug affects human beings record, researchers plan to enrol approximately 32 people, aged 21 to 70, who have undergone genetic testing for HD  and are classified as HD-ISS Stage 2 or mild Stage 3. The study is currently only recruiting in New Zealand, with additional study centres expected to be activated later on.

Participants will be assigned to receive SRP-1005 or placeboplacebo A placebo is a dummy medicine containing no active ingredients. The placebo effect is a psychological effect that causes people to feel better even if they’re taking a pill that doesn’t work. across four groups, with each new group receiving a higher dose than the one before it. Conducting an early trial with this type of “dose escalation” design can help to identify the right amount of drug as safely as possible. Treatment consists of three weekly subcutaneous injections, followed by monitoring through 24 weeks.

At this stage, the big question is safety, not whether SRP-1005 improves HD symptoms. Researchers will carefully track side effects and will also measure the amount of SRP-1005 found in blood, urine and CSFCSF A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord. to see how well the drug spreads through the body. The study is expected to run through late 2027.

More shots on goal

The history of HD drug development has taught us not to put all our eggs in one basket. Even treatments aimed at the same fundamental target, like HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15, can differ enormously in how they work, where they travel in the brain, how long their effects last, and how they are administered. That makes having multiple approaches in development a strength rather than unnecessary duplication. Every carefully designed clinical trialclinical trial Very carefully planned experiments designed to answer specific questions about how a drug affects human beings can teach the field something, including trials of drugs that ultimately aren’t good treatments for HD.

SRP-1005 is still at the very beginning of that journey. We don’t yet know how well it reaches different parts of the human brain, how much HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 it can lower, what dose will be appropriate, or whether repeated treatment will ultimately prove safe and beneficial. But INSIGHTT expands the range of technologies being tested against one of HD’s most important drug targets. If HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 lowering is going to become a long-term treatment for people with HD, effectiveness is only part of the equation. How safely, conveniently and equitably a treatment can be delivered will matter too.

For now, another HTT-lowering strategy entering human testing means another opportunity to learn, and another shot on goal for the HD community.

Learn more:

Full details of the INSIGHTT study including current eligibility criteria and recruiting locations, is available from ClinicalTrials.gov under study NCT07536061.

Summary: 

• The INSIGHTT Phase 1 trial has begun dosing SRP-1005, a new experimental treatment designed to lower production of the huntingtin (HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15) protein.
• SRP-1005 uses siRNAsiRNA A way of silencing genes using specially designed molecules of RNA – like DNA but made of only a single strand – that target the message molecules in cells and tell them not to make a certain protein to target HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 messenger RNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein., adding another distinct approach to the growing range of HTT-lowering strategies being tested in people.
• Unlike treatments delivered into the spinal fluid or directly into the brain, SRP-1005 is given by injection under the skin, potentially offering a less invasive and burdensome treatment option if the approach proves successful.
• INSIGHTT will enrol around 32 participants and is primarily testing safety and tolerability. It’s early days, but another modality in clinical testing means another valuable shot on goal for the HD community.