Present: Professor Norman Nevin (Chair), Mrs Debbie Beirne, Professor Martin Gore, Professor David Harrison, Professor Jim Neil, Rev Dr Lee Rayfield, Dr Adrian Lepper, Dr Richard Ashcroft, Professor Andrew Lever, Professor Nick Lemoine, Dr Caroline Benjamin.

Secretariat: Dr Monika Preuss, Dr Jayne Spink and Mr Daniel Gooch.

Observers (morning only): Dr Mike Brannan (DH), Dr Janet Gibson (DH)

Morning: Educational session:

Three educational talks were given to provide the committee with some additional background on various issues and techniques to do with antisense technologies. The three speakers and their talks were:

• Professor Finbarr Cotter: "Antisense"
  
• Dr Matthew Wood: "RNA interference: Biology and Application"
  
• Professor George Dickson: "Gene Correction Strategies via Antisense Modulation of Pre-mRNA Splicing"

Afternoon: Policy Session

This afternoon policy session was used to discuss a list of questions the Secretariat had prepared for the Committee to consider, covering the range of possible antisense therapies that may be used in clinical trials.

1. Synthetic antisense oligonucleotides to down-regulate the expression of undesired proteins (gene silencing)

Synthetic antisense oligonucleotides are used widely in phase I to III clinical trials, primarily in cancer trials and against infectious diseases such as HIV or hepatitis.

GTAC decided that all types of antisense applications should be reviewed by GTAC. There should be the possibility for expedited review of applications which use established methodologies. Applicants of antisense trial should be given the opportunity to request exemption from the DH Flagging Project, provided an appropriate justification can be given.

2. Length of molecule and degree of chemical modification

Most oligonucleotide compounds used in clinical trials are between 15 and 25 bases long. Most oligonucleotide compounds are chemically modified to make them more resistant to biological degradation.

GTAC decided that all applications using synthetic oligonucleotides irrespective of length, degree of chemical modification should be reviewed by GTAC.

3. Antisense DNA/RNA expressed in vivo via an expression vector

In contrast to synthetic antisense products discussed above, the active compound is not delivered directly but it is produced in the body by means of an expression vector.

GTAC decided that all applications using an expression vector for antisense DNA or RNA should be reviewed by GTAC, and should be subject to the Flagging Project.

4. Synthetic antisense oligonucleotides to modify a gene (gene correction)

In this scenario, antisense molecules are not being used to suppress protein expression but to modulate a gene.

GTAC decided that applications of antisense oligonucleotides for gene correction or modification purposes should be reviewed by GTAC, and should be subject to the Flagging Project.

5. Interference RNA and other new technologies (such as ribozymes)

These strategies are largely at the research stage, and not likely to go into clinical trials in the next few years.

Nevertheless, GTAC decided that any application of RNAi, or other new DNA or RNA technologies in the form of clinical trials, should be reviewed by GTAC.

Definition of gene therapy

As GTAC had clarified its position on antisense technologies, a rewrite of GTAC's definition of gene therapy, and accompanying list of inclusions and explanations, became necessary. The final agreed definition (signed off at the full committee meeting on 9 June) is as follows:

"The deliberate introduction of nucleic acids into human somatic cells for therapeutic, prophylactic or diagnostic purposes."

This definition is intended to incorporate all clinical trials involving the use of techniques for delivering synthetic or recombinant nucleic acids (DNA and RNA) into human subjects. Such techniques include, but are not limited to, the use of:

• genetically modified biological vectors (such as viruses or plasmids);
• genetically modified stem cells;
  
• oncolytic viruses;
  
• nucleic acids associated with delivery vehicles;
  
• naked nucleic acids;
  
• antisense techniques (for example, gene silencing, gene correction or gene modification);
  
• Genetic vaccines;
  
• DNA or RNA technologies such as RNA interference;
  
• xenotransplantation of animal cells (but not solid organs).

GTAC Secretariat
July 2004

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