#1 Clinical Trials Search in Europe

Single Guide Rna Targeting The Human Ttr Gene

NTLA-2001 is an innovative gene therapy drug being studied in clinical trials for the treatment of transthyretin amyloidosis (ATTR), a rare genetic disorder that affects the heart and nervous system. This article explores the ongoing research on NTLA-2001, which uses CRISPR/Cas9 technology to target the TTR gene responsible for the disease. The trials aim to evaluate the safety, efficacy, and long-term effects of this groundbreaking treatment in patients with different forms of ATTR.

Table of Contents

What is Single Guide RNA Targeting the Human TTR Gene?

Single Guide RNA Targeting the Human TTR Gene is a key component of an innovative gene therapy treatment called NTLA-2001. This therapy is being developed to treat a group of diseases known as transthyretin amyloidosis. NTLA-2001 is a type of in vivo CRISPR/Cas9-based genome editing therapeutic, which means it’s designed to edit genes directly inside the body.[1]

The treatment consists of two main parts:

  • Messenger RNA (mRNA) encoding for Cas9 protein (also known as ziclumeran)
  • Single guide RNA (sgRNA) targeting the human TTR gene

These components are delivered in a special lipid nanoparticle system, which helps them enter cells in the body.[1]

Medical Conditions Treated

NTLA-2001 is being developed to treat two main forms of transthyretin amyloidosis:

  1. Hereditary Transthyretin Amyloidosis with Polyneuropathy (ATTRv-PN): This is an inherited condition that affects the nerves, causing symptoms like numbness, tingling, and weakness in the limbs.[2]
  2. Transthyretin Amyloidosis-Related Cardiomyopathy (ATTR-CM): This form of the disease primarily affects the heart, leading to heart failure symptoms.[2]

Both conditions are caused by abnormal buildup of a protein called transthyretin (TTR) in various tissues of the body.

How It Works

NTLA-2001 uses a revolutionary gene-editing technology called CRISPR/Cas9 to target and modify the TTR gene in liver cells. Here’s a simplified explanation of how it works:

  1. The mRNA in the treatment provides instructions for cells to produce the Cas9 protein, which acts like a pair of molecular scissors.
  2. The single guide RNA (sgRNA) guides the Cas9 protein to the specific location of the TTR gene in the DNA.
  3. The Cas9 protein then cuts the DNA at this location, effectively “turning off” the TTR gene.
  4. With the TTR gene disabled, liver cells produce less of the problematic TTR protein, potentially slowing or stopping the progression of the disease.[1]

Administration

NTLA-2001 is administered as an intravenous infusion. This means it’s given directly into a vein. The maximum dose being studied is 55 mg, typically given as a single treatment.[2] Some studies are also looking at dosing based on body weight, with doses up to 1 mg/kg being investigated.[3]

Current Clinical Trials

Several clinical trials are currently underway to evaluate NTLA-2001:

  1. MAGNITUDE Study: A Phase 3 trial evaluating the efficacy and safety of NTLA-2001 in patients with ATTR-CM.[2]
  2. Long-Term Follow-Up Study: This study is monitoring the long-term safety and effects of NTLA-2001 in patients who have received the treatment in previous trials.[3]
  3. Phase 1 Two-Part Study: This study is evaluating the safety, tolerability, and early signs of effectiveness in patients with ATTRv-PN and ATTR-CM.[1]

Eligibility Criteria

While specific criteria may vary between studies, general eligibility factors include:

  • Age: Usually 18 to 80 or 90 years old
  • Confirmed diagnosis of ATTRv-PN or ATTR-CM
  • Certain levels of disease severity (e.g., specific scores on neuropathy or heart failure scales)
  • Adequate liver and kidney function
  • No access to or progression despite use of approved treatments for transthyretin amyloidosis[1]

Safety Considerations

As with any new treatment, safety is a primary concern. Some key safety considerations include:

  • Potential immune reactions to the treatment components
  • Liver function monitoring
  • Cardiovascular health assessment
  • Vitamin A supplementation may be required, as TTR is involved in vitamin A transport in the body[1]

Future Prospects

NTLA-2001 represents a groundbreaking approach to treating transthyretin amyloidosis. If successful, it could offer a one-time treatment that addresses the root cause of the disease. However, it’s important to note that the treatment is still in clinical trials, and more research is needed to fully understand its long-term efficacy and safety profile.[2][3]

Patients interested in this treatment should discuss it with their healthcare providers and consider participating in clinical trials if eligible.

Aspect Details
Drug Name NTLA-2001
Drug Type Gene therapy using CRISPR/Cas9 technology
Target Conditions Hereditary Transthyretin Amyloidosis with Polyneuropathy (ATTRv-PN), Transthyretin Amyloidosis-Related Cardiomyopathy (ATTR-CM)
Administration Method Intravenous infusion
Primary Objectives Evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics
Secondary Objectives Assess effects on neurologic function, quality of life, and long-term outcomes
Key Inclusion Criteria Adults 18-80 years, confirmed ATTR diagnosis, specific disease severity measures
Key Exclusion Criteria Other forms of amyloidosis, severe heart conditions, recent use of certain ATTR treatments
Trial Phases Phase 1, Phase 3, and long-term follow-up studies
Primary Endpoints Safety assessments, changes in serum TTR levels, cardiovascular outcomes

FAQ

  • What is NTLA-2001 and how does it work? NTLA-2001 is a gene therapy drug that uses CRISPR/Cas9 technology to target the TTR gene responsible for transthyretin amyloidosis. It consists of two main components: messenger RNA encoding Cas9 protein and a single guide RNA targeting the human TTR gene. This combination aims to edit the faulty gene and potentially reduce or stop the production of harmful proteins causing the disease.
  • What types of transthyretin amyloidosis are being studied in these clinical trials? The clinical trials are focusing on two main types of transthyretin amyloidosis: hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and transthyretin amyloidosis-related cardiomyopathy (ATTR-CM). These conditions affect the nervous system and heart, respectively.
  • What are the main objectives of the NTLA-2001 clinical trials? The main objectives of the trials are to evaluate the safety, tolerability, and effectiveness of NTLA-2001 in patients with ATTR. Researchers are also studying the drug's pharmacokinetics (how the body processes the drug) and pharmacodynamics (how the drug affects the body). Additionally, they aim to assess the long-term effects and potential improvements in patients' quality of life.
  • Who is eligible to participate in these clinical trials? Eligibility criteria vary between trials but generally include adults aged 18-90 with a confirmed diagnosis of ATTR. Participants must meet specific health requirements, such as certain levels of heart and kidney function. Some trials may exclude patients who have recently used other ATTR treatments or have certain medical conditions.
  • How is NTLA-2001 administered to patients in the trials? NTLA-2001 is administered as an intravenous infusion. The dosage and frequency may vary depending on the specific trial and patient characteristics. Some studies are exploring single-dose treatments, while others are investigating the effects of multiple doses over time.

Ongoing Clinical Trials on Single Guide Rna Targeting The Human Ttr Gene

  • Long-Term Safety Study of NTLA-2001 for Patients with Hereditary Transthyretin Amyloidosis with Polyneuropathy or Transthyretin Amyloidosis-Related Cardiomyopathy

    Recruiting

    4 1 1
    Investigated diseases:
    Investigated drugs:
    France Sweden

  • Study of NTLA-2001 for Patients with Transthyretin Amyloidosis and Heart Disease

    Not yet recruiting

    3 1 1
    Investigated drugs:
    Austria Belgium Czechia Denmark France Germany +8

  • Study on NTLA-2001 for Patients with Hereditary Transthyretin Amyloidosis with Polyneuropathy

    Not recruiting

    1 1 1
    Investigated diseases:
    Investigated drugs:
    France Sweden

Glossary

  • Transthyretin Amyloidosis (ATTR): A rare genetic disorder caused by abnormal buildup of a protein called transthyretin in various organs, leading to dysfunction of the heart, nervous system, and other body parts.
  • CRISPR/Cas9: A gene-editing technology that allows researchers to make precise changes to DNA sequences. In NTLA-2001, it's used to target and modify the TTR gene responsible for ATTR.
  • Polyneuropathy: A condition affecting multiple nerves throughout the body, often causing weakness, numbness, and pain in the hands and feet.
  • Cardiomyopathy: A group of diseases affecting the heart muscle, leading to reduced heart function and potential heart failure.
  • Pharmacokinetics: The study of how a drug moves through the body, including its absorption, distribution, metabolism, and excretion.
  • Pharmacodynamics: The study of how a drug affects the body, including its mechanism of action and therapeutic effects.
  • NT-proBNP: A blood marker used to assess the severity of heart failure and monitor heart function.
  • Intravenous Infusion: A method of delivering medication directly into a vein using a needle or catheter.
  • Single Guide RNA (sgRNA): A short RNA sequence that guides the Cas9 enzyme to a specific location on the DNA for gene editing.
  • Lipid Nanoparticle: A tiny particle made of fats used to deliver genetic material, such as mRNA and sgRNA, into cells.

References

  1. http://clinicaltrials.eu/trial/study-on-ntla-2001-for-patients-with-hereditary-transthyretin-amyloidosis-with-polyneuropathy/
  2. http://clinicaltrials.eu/trial/study-of-ntla-2001-for-patients-with-transthyretin-amyloidosis-and-heart-disease/
  3. http://clinicaltrials.eu/trial/long-term-safety-study-of-ntla-2001-for-patients-with-hereditary-transthyretin-amyloidosis-with-polyneuropathy-or-transthyretin-amyloidosis-related-cardiomyopathy/