About CMV

Cytomegalovirus (“CMV”), a member of the herpesvirus family, is extremely common worldwide. In the U.S., nearly 60% of individuals over the age of six are infected with CMV. CMV is transmitted through direct contact with infectious body fluids, including saliva, urine, or blood.

In most individuals, primary infection with CMV is asymptomatic, with the infected host showing no signs or symptoms of disease. Once an individual is infected with CMV, the virus lies dormant in infected cells and can remain that way for years before reactivating. CMV infection or reactivation can lead to serious complications in hosts whose immune systems are either compromised by disease or suppressed, which is common following stem cell and solid organ transplants.

Transplant Procedures

Hematopoietic stem cell transplants (“HSCT”) have demonstrated success in treating a range of conditions, including many cancerous and non-cancerous diseases of the blood. This procedure involves isolating stem cells from a donor and transferring them to a recipient. These stem cells can then differentiate into the types of blood cells needed for the recipient’s body and immune system to function normally. The stem cells can be derived from multiple donor sources, including bone marrow, peripheral blood, or umbilical blood.

One of the challenges in transplant procedures is the prevention of CMV infection. CMV infection is common following HSCT due to the immune suppression regimen that coincide with the transplant. Before the advent of prophylactic treatment, CMV reactivation occurred in 70-80% of CMV-seropositive HSCT recipients. Rates of reactivation are now significantly lower, but the treatment and prevention of CMV has significant side effects on patient morbidity and quality of life.

Patients who are CMV-seronegative are also at risk of contracting CMV from CMV-seropositive donors. The transplant of CMV-seropositive hematopoietic stem cells (“HSC”) into a CMV-seronegative recipient leads to CMV infection in approximately 30% of patients, and is associated with an increased risk of transplant-related complications.

Solid organ transplants are also indicated for a number of diseases and they can save the lives of patients with failing organs. CMV is a frequent cause of complication following solid organ transplant, with disease rates of 20-30% when the donor is CMV-seropositive and the recipient is CMV-seronegative.

Post-transplantation CMV disease can cause a wide range of symptoms and involve multiple organs. The virus often targets the transplanted organ, leading to a number of inflammatory and possibly life-threatening conditions. For instance, hepatitis can occur in liver transplant recipients while pneumonitis is frequent in lung transplant recipients. The disease can also cause problems in the gastrointestinal tract and the nervous system. Often, a syndrome characterized by non-specific symptoms such as fever, weakness, malaise, and a lowered white cell count in the blood occurs and may be difficult to distinguish from transplant rejection.

A surgeon performs a bone marrow harvest operation.

Post-transplant Lymphoproliferative Disorder

In some patients, CMV infection can contribute to a devastating disorder called post-transplant lymphoproliferative disorder (“PTLD”). PTLD is a rare but serious side effect of HSCT and solid organ transplantation disorder where the host’s immune cells proliferate uncontrollably following transplant immunosuppression. PTLD occurs in approximately 2% of HSC transplants, 3% of liver transplants, and up to 5% of heart transplants.

While Epstein-Barr Virus virus (“EBV”) is generally considered the cause of PTLD, CMV has been shown to increase the risk of developing PTLD. A mismatch of CMV serostatus between the recipient and the donor has been associated with a four- to six-fold increase in the risk of PTLD following solid organ transplant and a reported mortality rate of 40-70%. As such, interventions to reduce the risk of PTLD would significantly improve patient outcomes.

Standard of Care

Currently, antiviral drugs are used to prevent CMV infection following transplant procedures. The most commonly used antivirals are ganciclovir and valganciclovir. Ganciclovir in particular is effective at reducing CMV infections following both HSCT and solid organ transplant, reducing overall mortality in solid organ transplant recipients by 37%. However, ganciclovir has a number of side effects, including the suppression of the cells of the immune system, fever, nausea, vomiting, and gastrointestinal issues. Therefore, the benefits and side effects of ganciclovir must be carefully considered.

Opportunity

CMV is a common cause of complications following HSCT and solid organ transplant. Complications range from mild to fatal. Additionally, a transplant from a CMV-seropositive donor to a CMV-seronegative recipient is associated with an increased risk of CMV-related disease. Therefore, a treatment to deactivate CMV in donor cells before transplantation has the potential to significantly reduce both CMV-related disease and the side effects of CMV treatment in transplant recipients.

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