The University of Southampton

Author: Nelu Jayaweera

Alzheimer’s Disease Treatment: US-Targeted Microbubble Drug Delivery

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The stem cell and regenerative medicine workshop introduced me to a new advanced tissue engineering discipline: the use of microbubbles. I was fascinated to learn that many disorders are incurable due to drug delivery transport implications and that the development of microbubbles has the potential to solve many of these difficulties.

Microbubbles (MB) are non-toxic and biocompatible technological structures that interact dynamically with organs at the cellular level. They have a size of 0.1- 10 µm and can be destroyed by ultrasonic radiation (US). The US can be targeted to specific locations, improving selective therapy. Tissue engineering with biomaterials is an innovative and promising technique for increasing human life expectancy, and scientists are interested in integrating MBs with scaffold architecture.

A simple animation I created to explain the process of the US-targeted microbubble

Alzheimer’s disease (AD) is the most common cause of dementia. It affects around 50 million individuals globally, and its prevalence is expected to double by 2050. There are currently no treatments to cure Alzheimer’s disease, although the FDA has approved drugs to treat symptoms. E.B White, the author of my favourite childhood novel Charlotte’s Web, is a notable person who sadly died of Alzheimer’s disease. He has suffered by losing his freedom and forgetting his accomplishments.

Memory loss, reduced cognitive function, and behavioural instability are hallmarks of AD

Alzheimer’s disease is characterised by the production of Aβ senile plaques and the aggregation of tau-mediated neurofibrillary tangles. According to recent findings, eliminating amyloid β oligomers and plaques using monoclonal antibodies may stop progression. However, a challenge is the efficient delivery of therapeutic drugs across the Blood Brain Barrier (BBB) for the treatment of central nervous system (CNS) diseases. The BBB is a thin membrane formed by endothelial cells that removes 98% of small-molecule medications and 99.9% of large-molecule therapies for brain diseases, causing drug transport-related issues. The BBB presents a significant impediment to the delivery of medicines to the brain. Yet, the US-targeted microbubble destruction can promote the entry of therapeutic molecules into specific CNS regions, enhancing gene-carrier absorption in damaged brain areas while preventing the loss of normal cells.

Click on the image to watch a video explanation of the Morris water maze test

Zhu et al., (2022) investigated the efficacy of US-targeted microbubble destruction (UTMD) in the dual delivery of beta-amyloid (Aβ) antibodies carried by MBs and neural stem cell (NCS) of AD. They used 27 transgenic mice (Tg) and 33 wild-type mice, who were allocated into two groups: control and MB with AB and/or NSCs. The Morris water maze test was used to investigate cognitive and memory processes. As we learned in class, tissue engineering research employs knockout mice, which are a type of Tg. These are genetically engineered mice that receive foreign DNA. The difference between knockout mice and Tg is that the latter has a foreign gene introduced into their gene, e.g., AD. They discovered that the BB opened in Tg mice given a combination of NCS and Aβ antibody UTMD group. Their memory performance and spatial learning improved, and they discovered a reduction in Aβ plaques in the hippocampus and cortex.

(540) Focused ultrasound and microbubbles to overcome the blood-brain barrier for drug delivery – YouTube
A detailed video of how microbubbles work in the brain

In conclusion, the use of MB could open a  plethora of solutions to incurable diseases such as Alzheimer’s. However, further research needs to confirm its efficiency. For example, the US successfully destroyed MB, but what debriefs particles? Could it raise any side effects? Furthermore, given that dementia primarily affects the elderly, some individuals may underestimate the importance of discovering a cure for AD. E.B. White did pass away from old age. Throughout my research, I came across the Alzheimer’s Society website, which collects real-life accounts of dementia patients. I’ve noticed that diagnosis is made to one but it affects the entire family. E.B. White’s son would read him his very popular books, to then be asked who the author was. Alzheimer’s is an emotionally and physically draining disorder that affects members of a family, thus treatment is sought to lessen the pain of diagnosed patients.

A Better Solution for Human Cloning: The CRISPR/Cas9 Technology

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Cloning is the technique of generating organisms that are exact genetic duplicates of one another. Scientists’ major goal is to discover the “ultimate code” that produces a “perfect” organism – a body free of diseases and anomalies. Cloning, in this opinion, is beneficial in reducing the spread of fatal inherited disorders. Dolly the sheep was the first organism to be successfully cloned.

Cloning Process of Dolly the Sheep

This case intrigued the psychologist in me, who wondered why some scientists are so eager to legalize this process when Dolly’s case was the 277th attempt. Thus, the unsuccessful 276th attempts have either failed to develop into a viable embryo or been aborted after they showed signs of abnormality. Such, high chances of failure with the accompanying issues of wastage of human embryonic material are not acceptable. However is it correct to think that cloning does not happen in the scientific community?

The Two types of Human Cloning

There are primarily two methods of cloning in which an embryo is formed other than by sperm fertilisation of an egg. Embryo splitting, also known as reproductive cloning, is a method of artificially stimulating the natural process of producing identical twins. This type of cloning was used in the production of Dolly. Somatic cell nuclear transfer or ‘therapeutic cloning’ is the only process capable of generating clones of living humans. It is a sort of non-reproductive cloning used to obtain stem cell lines for research. Stem cells are undifferentiated cells that can self-renew or develop into multiple cell types. Stem cells are classified into two types: multipotent stem cells (also known as “adult cell cells”) and pluripotent stem cells (also known as “embryonic stem cells”). The latter are derived from early embryos and have seen extensive study use.

The process of reproductive cloning is as follows: all genetic material carried by a single ovum (egg) is contained within a nucleus; if this nucleus is removed (ovum enucleation) and then replaced with the nucleus of a somatic cell (from the body of an embryo), an embryo genetically identical to the donor of the somatic cell nucleus can be created. The resultant embryo is subsequently implanted into a surrogate mother’s womb for gestation and delivery. The described approach has been applied in a process called ‘three-parenting IVF’. It enables women with mitochondrial disease to have a genetically related child free of the disease.

The mitochondrion has its own genome, the mtDNA, which encodes 13 proteins that are subunits of respiratory chain complexes. Mutations stop the mitochondria from converting food and oxygen into food, affecting negatively the heart, brain, and lungs. Dysfunctional mitochondria are implicated in several neurodegenerative diseases including Parkinson’s disease. Therefore, ‘three-parenting IVF’, or mitochondrial transfer in IVF could be considered an effective preventive strategy. However, it crosses ethical boundaries as it interferes with germ-line, not to forget the psychological and social implications.

Nevertheless, the CRISPR/Cas9 technology could be regarded as a better solution. It has grown in prominence due to its low cost and possible applicability in the treatment of genetic diseases. It is capable of strong gene editing. However, it may not affect all mtDNA, but it may change enough to lower the individual’s illness threshold, offering therapeutic benefits. This innovative technology could be utilised to treat diseased people as well as IVF embryos prior to implantation. It provides a reduction in mutation load, which lowers symptoms and disease burden. The CRISPR/ Cas9 editing of embryonic mtDNA may appeal as a more socially acceptable option to ‘three-parenting IVF’. Rather than merging the genetics of three people, it allows a couple to conceive without the need for donor genetic material.

The video shows the process of CRISPR/Cas9

The logic of human cloning and the logic of therapeutic cloning are identical; the spare embryo is created to expire. Nevertheless, a much better alternative could be the CRISPR / Cas9 gene editing technology, which attempts to cut off parts of defective DNA and subsequently reinstall it in the embryo. It can lead to reduced mtDNA disease, perhaps saving many affected people.

Reference list:

Brand, M.D. and Nicholls, D.G. (2011) Assessing mitochondrial dysfunction in cells, The Biochemical journal. U.S. National Library of Medicine. Available at: https://pubmed.ncbi.nlm.nih.gov/21726199/.

Gurnham , D. (2016) The mysteries of human dignity and the Brave New World of human cloning …, Sage Journals . Available at: https://journals.sagepub.com/doi/abs/10.1177/0964663905051219.

How CRISPR let you edit DNA (2019) YouTube. YouTube. Available at: https://www.youtube.com/watch?v=6tw_JVz_IEc.

José , V.D. (2008) Cloning humans, cloning literature: Genetics and the imagination deficit, New genetics and society. U.S. National Library of Medicine. Available at: https://pubmed.ncbi.nlm.nih.gov/17256208/.

O’Mathúna, D.P. (2002) What to call human cloning – EMBO press, Viewpoint. Available at: https://www.embopress.org/doi/full/10.1093/embo-reports/kvf122.

Rulli , T. (2016) What is the value of three-parent IVF?, The Hastings Center report. U.S. National Library of Medicine. Available at: https://pubmed.ncbi.nlm.nih.gov/27198755/.