Project call for a research project on unintended germline modification in new gene therapies

Address project bids to: F. van der Wilk, General Secretary COGEM;

The Netherlands Commission on Genetic Modification (COGEM) commissions third-party research to support its work. The present project is a collaboration with the Central Committee on Research Involving Human Subjects (CCMO). Interested parties are invited to submit a project bid.

Subscription to open projects is unconditional and open to any interested party. The commission aims to receive at least three bids per project.

The project bid must at least contain a clear description of the proposed work and an insightful budget. This means that there must be a clear link between the budgeted costs and the proposed work stating the number of estimated hours and a breakdown of hourly rates.

Research projects will be supervised by an expert committee. This guidance committee will meet at least three times in the presence of the research performers. The research performers will present the results of their research in a meeting of one of the subcommittees of COGEM and in the CCMO.

The COGEM Executive Board makes the decision on allocation of projects. Proposals are evaluated on the following criteria:

– degree of alignment with the research question;

– competence of the research team to carry out the proposed research;

– clarity and (scientific) quality of the proposed research;

– (feasibility of) the work program;

– price and cost-effectiveness.

The following project is open for enrollment:

Title: Germline modification and new gene therapies; an exploration

Gene therapy is on the rise. Great successes have been achieved particularly in the treatment of blood cancers and some very serious hereditary diseases. Thirteen gene therapy treatments have now been admitted to the market in the EU, and the number of clinical trials involving gene therapies has increased significantly in recent years. Current gene therapies are based on viral vectors derived mainly from lenti- and retroviruses and adeno-associated viruses (AAV). These genetically modified (GM) viruses can be administered directly to a patient or used to modify cells that are taken from the patient, after which the cells are returned to the patient.

In gene therapy, only somatic cells are modified. Modification of sex cells (germline modification) is prohibited, because this would genetically modify the human itself and the modification would be passed on to any offspring. Unintended germline modification by gene therapy seems to be excluded when using viral vectors. Though viral DNA can be detected in the semen of patients and experimental animals after administration of GM-AAV vectors, the vector is in the fluid or lymphocytes present therein and not in the sperm cells. The GM viruses appear unable to cross the germline barrier. As a result, attention to the risk of inadvertent germline modification has faded in recent years.

Meanwhile, other forms of gene therapy are rapidly being developed. The first CRISPR-Cas gene therapy has been licensed in the United Kingdom and the United States, and there is busy experimenting with RNA applications. Many of the new gene therapies no longer rely on viral vectors and packaging the genetic material into virus particles to enter the cell. The genetic material to be inserted is wrapped in liposomes, lipid nanoparticles, polymers, etc., among other things. This avoids problems such as insufficient capacity of viral vectors to incorporate genetic material, high production costs and the challenge of producing enough viral vector material.

However, the use of these non-viral “gene delivery” systems raises questions as to whether they could cross the germline barrier. It is known that germ cells and somatic cells in the gonads communicate with each other via so-called gap-junction connections, endocytosis and extracellular vesicles. In this way nutrients, hormones, proteins and small RNAs are transported to the sex cells. Since extracellular vesicles can reach sex cells and transfer their contents, the possibility cannot be ruled out for now that, for example, a lipid anode particle with a CRISPR-Cas construct could also do this.

Research question: COGEM, in collaboration with CCMO, would like to conduct an inventory of the latest knowledge on germline barrier transport, the available data on non-viral delivery systems, data on unintended germline modification in animal experiments, data on possible biodistribution to gonadal tissue/sex cells and unintended germline modification from clinical trials with CRISPR-Cas in humans, and to have an analysis made of the possible likelihood of germline modification based based on these data. COGEM and CCMO also want to gain insight into the requirements of other authorities regarding preclinical data on germline transmission before proceeding with ‘first in human’ studies.

Purpose: Gain insight into the likelihood of unintended germline modification in new gene therapies to support risk analysis.

Type of research: Literature study