Challenges of Gene Therapy Regulation

Gene therapies from a conceptualization perspective have been around since Aristotle deduced that heredity must somehow be impacted through contributions from both mother and father. Given the contributions of Mendel and others since then, it has become readily apparent that the ‘devil is in the details’ with respect to correction of genetic abnormalities that lead to detrimental clinical phenotypes. Lately, there has been much focus on development and clinical utilization of gene therapies to not only lessen the impact of, but ultimately to eliminate the phenotypic effects of heritable disorders, especially within the Orphan Disease space.

However, the challenges associated with gene therapy regulation are many; whether in vivo or ex vivo methodologies are utilized the basic science associated with introduction of successful clinical gene therapies cannot be ignored. For our purposes here today, I present to you the following challenges (and opportunities for improvement) that must be addressed before even testing new gene therapies in human populations – for the purposes of this posting I assume that gene therapy is essentially limited to gene editing. That is, introduction of a copy of a functioning wild type gene for a monogenic disorder, as opposed to gene expression modulating technologies such as RNA interference.

Here’s the list: 

1)   Choice of the appropriate gene trafficking vector (whether AAV, nanoparticles or otherwise)

2)   Mode of introduction (IV infusion, subcutaneous injection (manipulated stem cells included))

3)   Targeting to organs/tissues of interest

4)   Survival from immune mediated destruction in systemic blood/plasma

5)   Regulation of entry into the appropriate cell type

6)  Intracellular localization of the gene carrying vector once entry into the appropriate cell type is achieved

7)   Survival from ubiquitin mediated or other destructive mechanisms in the cell

8)   Entry into the cellular nucleus, which in and of itself is highly regulated

9)   Integration into chromatin in a place where destruction/mutation of cellular physiology coded genes are not disrupted. This includes not inappropriately impacting expression of proto-oncogenes

10) Expression of the newly introduced gene is regulated at the appropriate transcriptional (and subsequently translational) levels

11) Alternative splicing mechanisms are regulated such that the complete (or required) elements of the newly integrated wild type gene are appropriately utilized to manufacture functional proteins

12) Then there is the question of post-translational modifications, which most certainly are required to direct intracellular trafficking, secretion of the protein if required, and non-destruction of the (replacement) protein

This list is not meant to be exhaustive and the associated challenges, while substantial, not insurmountable, and there are several promising gene therapies in developmental and clinical phases of commercialization today. Notwithstanding the recent withdrawal of Glybera in the EU market, there will likely be several new gene therapies approved for marketing in the US within the next 3-5 years (not including CAR-T immunotherapies which may be available within the next 1-2 years). My point here is to illustrate that from a regulatory science perspective, each of the above considerations introduces an element of risk into the utilization of new gene therapies in the clinical setting. Ideally, the regulatory science should precede the introduction of new technologies; however, in this case, I believe that we are being reactive rather than proactive with regard to regulating the introduction of these therapies. As with all of you, I believe that maximizing the benefit to risk profile should be the first priority and I know that we will seek to achieve this as we move forward.

Would love to hear feedback, either through LinkedIn or through [email protected].