210701P - ETHICS OF CONDUCTING GENE THERAPY STUDIES

Presented at a workshop on the Ethics of Early Phases of Clinical Trials and Gene Therapy’ held at the King Abdulaziz City for Science and Technology on July 1, 2021, at 9.00am by Dr Omar Hasan Kasule Sr MB ChB (MUK), MPH (Harvard), DrPH (Harvard) Professor of Epidemiology and Bioethics, Member and former Chair Institutional Review Board, Member and former Chair Human and Medical Ethics Committee, King Fahad Medical City, Riyadh.

 

Keywords: Review of ethics, risk/benefit of different types of gene manipulations in research
 
CONCEPTUAL BASIS

· The purpose of science is to search for causality relations (السببيبة) between and among phenomena so that the human can use these relations to deliver benefit (جلب المصلحة) or prevent harm (دفع المفسدة).

· Causality reflects the stability of physical laws (ثبات سنن الكون)[1] which is accompanied by stability of social laws[2].

· Overlying all this stability is an ethical framework laid down by the Creator that gene therapy and its research must obey.

· Gene therapy and its related clinical trials must aim at correcting environmentally caused damage to the perfect creation but not pretend to interfere with that creation. Any changes must follow the laws of change (سنن التغيير)

 

APPLICABLE ETHICAL THEORIES AND PRINCIPLES: Human dignity

· Human dignity[3]  (كرامة االانسان) protects from speculative research that is not responding to severe disease.

· Humans cannot be subject to the type of genetic manipulation that occurs in animals and plants without strong justification.

· Some of these manipulations may arise out of human pride to change the created order for no reason and out of misguidance[4].

· Human dignity also requires that genetic research and manipulation respect and do not unnecessarily invade the privacy of the individual, the family, and the community (ancestors and descendant).

 

APPLICABLE ETHICAL THEORIES AND PRINCIPLES: Life and Health  (نفس)

· Preservation of life and health (حفظ النفس) requires that genetic disorders are considered medical conditions that require research to look for their treatment.

· Both genetic disorders and their treatment are part of Allah’s pre-determination (قدر).

· The genetic trial should not have major adverse consequences for life and health.

 

APPLICABLE ETHICAL THEORIES AND PRINCIPLES: Progeny (نسل)

· Preservation of progeny (حفظ النسل) requires that research be carried on somatic genetic diseases to allow children to grow into healthy adults who will in turn reproduce the next generation.

· However, germline therapy and research are prohibited by several jurisdictions because of unknown and unforeseeable future generational risks.  

 

APPLICABLE ETHICAL THEORIES AND PRINCIPLES: Resources (مال)

· Preservation of resources (حفظ المال) requires posing the question whether costly genetic therapy trials are a priority over more common diseases that are cheaper to prevent and treat.

· Gene therapy trials must therefore incorporate cost-benefit, cost-effectiveness, and cost-utility analyses.

 

APPLICABLE ETHICAL THEORIES AND PRINCIPLES: Minimizing harm-1 (دفع الضرر).

· Unlike conventional supra-genomic research, gene therapy research has more serious unknowable present and future risks to the genome which is the biological essence of the human and raises several ethical issues arise.

· Is gene therapy animal research preceding human research necessary given that findings in animals may not apply to the human genome?

· Can phase 1 studies be carried out on healthy volunteers using genes given the high risk whereas patients can expect at least some benefits? Can such studies be undertaken if chemicals such as an aminoglycoside is used?

APPLICABLE ETHICAL THEORIES AND PRINCIPLES: Minimizing harm-2 (دفع الضرر

· Is consent from the participant enough or should the relatives also be involved because of the risk of breach of family confidentiality and future generational effects?

· Is consent informed valid given that the participant may not understand the complex genetic information and the many gaps in the knowledge about the genome that the researcher cannot answer?

· What extra measures will be taken to maintain confidentiality in view of the higher risks of breach of family genetic secrets?

· Should the participant give consent in advance to disclosure of incidental findings?

 

ETHICAL ISSUES OF DIFFERENT GENETIC MANIPULATIONS: Replace the missing substance:

· This option will remove the need for unnecessary gene manipulation (not ضرورة). Once we have a working treatment it is better to prevent harm than to accrue a benefit (دفع المفاسد مقدم علي جلب المصالح).

· There is a counter argument that we should go to the root cause (the genetic defect) and not deal with downstream events[5].

· Replacement can be in the form of providing the substance or implanting a cell that will produce it.

· Substance replacement by pancreatic enzyme replacement can prevent malnutrition in cystic fibrosis[6] and tyrosine supplementation in phenylketonuria[7].

· Cell therapies have been tried in muscular dystrophies[8] and beta thalassemia[9]

 

ETHICAL ISSUES OF DIFFERENT GENETIC MANIPULATIONS: Modify the defective gene activity

· Modification is by inhibition, enhancement, modulation, etc

· Modulators of the mutated CFTR (cystic fibrosis transmembrane conductance regulator) gene with/without potentiators have shown clinical improvement in cystic fibrosis[10], [11].

· The approval of 2 modulators, LUM and IVA, by USFDA in 2015 was followed by reduction of cystic fibrosis morbidity and mortality[12].

· Drugs have been developed to enhance the expression of the γ-gene to result in increase of fetal hemoglobin (HBF) and hence total hemoglobin[13] or by down regulation of BCL11A which is a repressor of the γ-gene[14].

 

ETHICAL ISSUES OF DIFFERENT GENETIC MANIPULATIONS: Replace the defective gene:

· Gene replacement therapy is inserting DNA in a cell to enhance/disrupt the expression of a protein.

· The insertion is by putting the DNA in the genome of the vector and letting the vector enter the cell and transfer the DNA to the cell’s genome.

· The gene of the inserted DNA replaces the defective gene for example a functional human F9 gene can be inserted into liver cells of hemophilia patients[15].

 

ETHICAL ISSUES OF DIFFERENT GENETIC MANIPULATIONS: Replace the defective gene:

· Viruses are the commonest vectors used but other vectors can be used such as stem cells that are used in thalassemia and sickle cell disease[16] or transport proteins such as GalNAc transporters to liver cells. Naked DNA can also be injected.

· Adenoxine associated viruses (AAV) have the advantage of not integrating into the host genome (can be carcinogenic) and low immunogenicity[17]. The blood brain barrier impedes the passage of vectors[18], [19] and alternatives are sought.

 

ETHICAL ISSUES OF DIFFERENT GENETIC MANIPULATIONS: Replace the defective gene:

· Sickle cell disease is an autosomal recessive disorder in which the normal phenotype can be restored with only one copy of the normal gene[20].

· Lentivirus vectored gene transfers yield high hemoglobin levels with low genomic integration in the treatment of beta globinopathies[21].

· Duchenne muscular dystrophy is due to mutations in the X-linked dystrophin gene leading to loss of dystrophin protein but there are currently no effective treatments[22].

· Gene transfer studies are being undertaken[23]

 

ETHICAL ISSUES OF DIFFERENT GENETIC MANIPULATIONS: Edit the defective gene:

· CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) is a gene-editing platform that enables altering the nucleotide sequence in a living cell[24].

· Studies have been carried out on editing genes of 2 monogenic conditions thalassemia and sickle cell disease[25]. Improvement of SCD patients were seen after gene editing[26].

· Changes were observed to persist in edited hematopoietic cells[27]

 

NOTES:
[1] Surat Yasin: 40
[2] Surat Fatir: 43, Ahzab 62, Isra 77
[3] Surat Isra:70
[4] Surat Nisa: 117-121
[5] Blood Adv. 2020 Jul 28;4(14):3457-3465.
[6] Cochrane Database Syst Rev . 2020 Aug 5;8(8):CD008227
[7] Cochrane Database Syst Rev. 2021 Jan 4;1(1):CD001507.
[8] J Clin Invest. 2020 Nov 2;130(11):5652-5664.
[9] Cochrane Database Syst Rev 2021 Apr 21;4(4):CD008708.
[10] Int J Mol Sci. 2020 Aug 16;21(16):5882 
[11] J Cyst Fibros . 2021 May;20(3):452-459.
[12] Cureus. 2020 Dec 24;12(12):e12251. 
[13] Biomed Rep. 2020 Nov;13(5):48.
[14] N Engl J Med. 2021 Jan 21;384(3):205-215. 
[15] Blood. 2021 Feb 11;137(6):763-774.
[16] Transfus Apher Sci. 2021 Feb;60(1):103061.  
[17] Mol Ther. 2021 Feb 3;29(2):464-488. 
[18] Pharmaceutics. 2020 Dec 15;12(12):1216.
[19] Hum Gene Ther. 2021 Apr;32(7-8):349-374. 
[20] Cochrane Database Syst Rev . 2020 Nov 30;11:CD007652.
[21] Mol Ther. 2021 Apr 7;29(4):1625-1638.
[22] Genes (Basel). 2020 Jul 23;11(8):837.
[23] JAMA Neurol. 2020 Sep 1;77(9):1122-1131. 
[24] J Biomed Res. 2020 Nov 9;35(2):115-134.
[25] N Engl J Med . 2021 Jan 21;384(3):252-260. 
[26] N Engl J Med . 2021 Jan 21;384(3):252-260.

[27] Stem Cells Transl Med. 2021 Mar 5.