Rambam Hospital Pioneers CRISPR Gene Therapy Trial for Cardiac Amyloidosis
Key Insights
Rambam Health Care Campus has initiated the first trial of Intellia Therapeutics' CRISPR-Cas9 gene therapy (search) for transthyretin cardiac amyloidosis (search) (ATTR-CA (search)), marking a shift toward treating non-hereditary diseases with gene editing.
The therapy targets liver cells to permanently disable the gene producing misfolded proteins that cause heart failure (search), offering potential one-time treatment for a condition affecting 5% of heart failure patients.
CRISPR gene editing is expanding beyond rare genetic diseases to treat age-related conditions, with promising trials also underway for high cholesterol (search) using similar mechanisms.
Rambam Health Care Campus has become the first medical center to trial a groundbreaking CRISPR-Cas9 gene therapy (search) developed by Intellia Therapeutics for transthyretin cardiac amyloidosis (search) (ATTR-CA (search)), representing a significant expansion of gene editing applications beyond rare hereditary diseases to treat age-related conditions.
The clinical trial, led by Dr. Oren Caspi, Director of the Heart Failure (search) Unit and Head of Rambam's Cardiovascular Research and Innovation Center, alongside Dr. Sirouch Petcherski and Dr. Aharon (Ronnie) Abbo, targets a disease that affects an estimated 5% of patients diagnosed with heart failure.
Revolutionary Treatment Mechanism
ATTR-CA (search) occurs when proteins fail to fold properly due to genetic defects or, more commonly, aging. These misfolded proteins accumulate in the heart, causing heart failure (search), cardiac arrhythmias (search), and potentially death. "When I studied medicine, this disease was considered serious and even terminal," Caspi explains, noting the rapid therapeutic developments in recent years.
The CRISPR-based therapy exploits two key characteristics of the disease that make it ideal for genetic editing. First, the body can function without large amounts of the problematic protein, allowing its production to be safely halted. Second, the protein is manufactured in the liver, an organ that readily absorbs genetically modified therapies.
The treatment works by reaching liver cells and splicing out the defective gene responsible for producing the disease-causing protein. Once administered, the genetic modification is irreversible, offering the potential for long-term benefit as a one-time treatment, though periodic maintenance may be needed in some cases as liver cells regenerate.
Clinical Administration and Safety Profile
Patients receive the therapy intravenously following immunosuppressive treatment to prevent immune responses to the drug delivery system. "We know that the body can have an immune response, not to the drug itself, but to the envelope in which the drug is delivered," Caspi explains. The immunosuppression is only required during the treatment course.
Preclinical animal studies have demonstrated no unintended genetic changes beyond the targeted gene modification. "We strongly believe in the safety levels of the product, but of course this is also part of what is tested in the trial," Caspi notes.
Expanding Applications Beyond Cardiac Disease
The success of CRISPR technology in treating ATTR-CA (search) has opened pathways for addressing other age-related conditions. Intellia Therapeutics, along with companies including CRISPR Therapeutics, Beam Therapeutics, and Verve (search) (expected to be acquired by Eli Lilly for $1-1.3 billion), are developing similar approaches for hypercholesterolemia (search).
In cholesterol treatment, the therapeutic strategy targets genes encoding proteins that regulate cholesterol levels, designed to replicate naturally occurring genetic mutations that result in lower cholesterol production without harmful health effects. Initial trials by CRISPR Therapeutics, with results published in May, demonstrated substantial reductions in patients' levels of "bad" cholesterol and triglycerides, with no problematic side effects observed.
Clinical Impact and Future Prospects
The therapy's potential for early intervention is particularly significant. When administered before heart failure (search) develops, the treatment can prevent disease progression entirely. For older patients, the prospect of infrequent treatment offers substantial advantages over complex, ongoing drug regimens.
"This is really personalized medicine, which can bring about a complete change in the course of the disease, and we are interested in helping additional patients as part of the research that continues to take place at Rambam," states Dr. Abbo.
The development represents a paradigm shift from treating only rare genetic diseases to addressing common age-related conditions through gene editing, potentially transforming therapeutic approaches for millions of patients worldwide. Verve (search) is expected to present results from larger cholesterol trials in the coming months, using slightly different mechanisms for gene-edited cholesterol reduction.
Regulatory Landscape
Gene therapy approvals will continue through the FDA's Center for Biologics Evaluation and Research, recently under the leadership of Dr. Vinayak "Vinay" Prasad, known for setting rigorous requirements for pharmaceutical companies. Despite recent political turbulence affecting his position, his stringent approach may ensure thorough testing while potentially affecting market timeline for these innovative treatments.