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Science in MPS and ML

14 Sep, 2020

Gene Therapy Updates and Pharmacological Presentations
Matthew Ellinwood, DVM, PhD
CSO, National MPS Society

Dr. Matthew Ellinwood spoke on advances in a subset of gene therapy that involves gene editing. Gene editing involves the targeted and sequence specific editing of genomic DNA in a patient or a patient’s cells. Various methods exist involving systems developed from discoveries by scientists studying the primitive “immune” system of bacteria, specifically bacteria that have evolved the ability to selectively recognize and cut up “foreign” DNA sequences. This has given research scientists a gene editing tool kit, many of the components of which the average person may have heard of in the news – systems like TALENs, zinc fingers nucleases, and the better known CRISRP-Cas system. This ability to edit DNA sequences is specific or “directed” in that the proteins that cut the cell’s DNA can be targeted to specific DNA sequences by either “programmed” proteins or sequences of RNA that recognize a target DNA sequence. Once a cell’s DNA is cut, scientists and research clinicians can genetically engineer and design sequences that are preferentially inserted into the site of DNA sequence, thereby changing or editing the normal sequence.

There are three chief limitations to this method with reference to the MPS and ML disorders: 1) The process is not 100% accurate and there are always concerns that “off target” cutting could generate pathological sequence changes; 2) The process is not very efficient at this point, so that targeting a patient’s specific genetic variation many only correct a very small percentage of the cells of the most easily targeted tissue such as liver; and 3) The therapeutic efficiency is too low to be viable for diseases involving membrane bound proteins (MPS IIIC, and ML II and III). Regardless of these limitations there is still much reason for enthusiasm regarding this approach. Rapid progress is underway improving the safety and specificity of these tools. Also, if researchers target a specific locus (i.e. a particular gene in the genome), such as the very transcriptionally active locus for the highly expressed liver protein albumin, they can introduce a secreted MPS enzyme associated enzyme to be produced at the same high levels as albumin. This approach aims to turn liver cells into a “factory” to pump out enzyme, similar in concept to the way a more conventional gene therapy might, or indeed the way a transplant does by replacing bone marrow as a source of secreted enzyme. This approach of targeting the albumin locus with gene editing is exactly the approach being pursued by Sangamo Therapeutics in clinical trials for MPS I and MPS II. At the current time, the efficiency of these tools do not provide a clear path to therapy for the MPS IIIC, and ML II/III community, but should there develop a soluble enzyme approach to treat these diseases, the same technology could be used for these underserved disorders.

Dr. Ellinwood also spoke on novel treatment approaches involving drugs. This is a very rich topic, but to provide a synopsis, drugs could be used in both a novel or conventional method. In most cases these drugs may provide only a marginal beneficial effect, but such effects could be clinically very beneficial depending on the effect, the patient’s gene variant, what other therapy may be being pursued, and the tissue, or signs or symptoms being targeted. Drugs that stabilize the production of an enzyme or improve its function and activity somehow are termed pharmacological chaperones, or simply chaperone therapy. These drugs “chaperone” the enzyme, allowing it to form normally or preserving its structure in ways that improve its activity. Drugs that target a specific kind of gene variant (so called stop codon mutations) are the focus of stop codon read through drug development. The idea is that these drugs will allow a cell’s protein production machinery to “push through” a stop codon, thus producing a protein.

Other approaches involve drugs that interrupt some aspect of pathology, such as bone disease or bone pain. Such drugs have been studied in both animal models and are in clinical trials in some cases. Such trials can involve approved drugs used for disease such as rheumatoid arthritis. Related to this approach of blunting the body’s response to some aspect of complex tissue pathology, are drugs that target something even more specific to the basic functions of a cell that may be disrupted in the MPS and ML disorders. This approach involves novel drugs or drugs that are being used in a novel way that seek to influence the normal function of a cell’s vesicles in such a way as to minimize the effect of the lysosomal storage seen in the MPS and ML disorders. This approach is often focused on a cell process known as autophagy (literally self-eating in Greek but referring to cell scavenging and recycling) which is a process closely linked to lysosomes and their function. There is tremendous promise in this area to develop drugs that could provide a viable treatment with significant benefit for some patients. However, such approaches still require a lot of science and research to fulfil their potential. Especially critical to this particular area of research are reliable and robust methods to identify known drugs (so called repurposing drug screens), that are rapid, efficient, accurate, and scalable, so that they can truly be high throughput, screening hundreds or even thousands of drugs as part of screening studies.