Genes and a cure for HSP – what is the connection?
A plain English explanation
… partly from Mark Weber of the SP Foundation, USA with additional information and editing by Frank McKeown, HSP Research Foundation.
Why find genes in the 1st place? How does it help toward our goal of finding a cure for HSP?
Genes make proteins.
Proteins do the work in cells (including nerve cells) that needs to be done to keep cells alive and to enable them to do their assigned jobs in our bodies.
Mutated genes make defective proteins.
Defective proteins don’t do the job that they are supposed to do, and sometimes do or cause things that are harmful, such as being toxic to a cell.
Discovering genes is discovering proteins. HSP is caused by defective proteins.
Scientists are now studying what HSP related proteins actually do in nerve cells (neurons). This is part of the new field of Proteomics. Scientists are discovering that several HSP related proteins actually work together — not surprising that they operate in the same biochemical pathway to get a job done. In fact one HSP related gene was discovered by a scientist looking at a protein that worked with a known HSP-related protein.
Research & Discovery
Researchers do get together. They do it in meetings. They do it in newly formed collaborations where someone with expertise in a newly relevant field is brought in to move the group forward faster. You can see it in the grant proposals that the SPF gets every year — proposals from scientists doing work in other fields that all of a sudden become relevant to HSP research because of some new research finding. The SP Foundation funded one of these scientists, Dr. Peter Baas of Drexel University, who was doing work on one protein but found another protein that did the same thing — Spastin (the 1st HSP related protein ever discovered). He is now focusing on Spastin and has become an HSP researcher. There are other scientists joining the quest for a cure as other breakthroughs make their existing work relevant to HSP research.
There have been several scientific papers already published that try to link many HSP related proteins to show how they work together to get a job done (when the proteins are normal), and how a defect in any one of them upsets their work — leading to HSP. We have come a long way since the 1st HSP related gene was identified in late 1999. Work is progressing on how the gene products (proteins) function, how they interact with other proteins, and how defects in certain proteins cause HSP.
The science is getting increasingly complex and difficult to understand for the average person. The research being carried out in the USA, Canada, England, France, Germany, Italy, Norway, China, Japan and Australia, as well as Finland, Estonia and other countries, is together making significant progress towards a cure. New and different fields and disciplines are coming together and collaborating in the process of discovering and understanding the critical functioning at the cellular and molecular levels of HSP.
New thinking – New possibilities
As knowledge accumulates, different potential pathways to finding a cure emerge. For example, the Stem Cell Pilot Study at Griffith University in Queensland in 2008 led the researchers to a novel way of thinking about the potential pathway to a cure, and it is this. All HSPers are born with a genetic mutation, however most do not develop symptoms until well into adulthood, and some never develop symptoms to any appreciable degree at all. This means that there is a compensation or workaround mechanism in play that does the job that is usually done by the normal gene in someone without HSP. This mechanism breaks down or becomes ineffective at some point in most people with HSP and symptoms start to develop. So this then leads to the thought that a cure might be possible if the compensatory mechanism can be continued and perpetuated, which might be a vastly different focus than trying to fix what is broken. It is all about possibilities – and we all have reason for some confidence that somewhere, sometime in the not too distant future, a researcher will discover what needs to be known to develop a cure.
In late 2016, the Griffith University research team led by Prof Alan Mackay-Sim and funded by this Foundation, after eight years of investigation, completed studies that identified drug compounds that restored function in SPAST HSP affected cortical neurons to near-normal levels. These cortical neurons were derived from stem cells that were grown in the laboratory from nasal tissue samples taken from people identified with SPAST HSP. Read more about the research timeline.
Covering the history and direction of research into HSP and similar diseases
History and Context
The discovery of new drugs is not only the province of the big drug companies. In NSW, for example, there are two Universities and a hospital-based research laboratory working together on the rapid synthesis and screening of molecules for therapeutic properties of interest. Such activities around the world are born out of the awareness that the pharmaceutical companies have generally failed to deliver solutions for Rare Diseases. HSP is one of the 6,000 rare diseases listed with NORD – the National Organization of Rare Diseases. In the US, NORD receives large sums from Government and corporations and also via their own fund raising activities for the purpose of research into rare diseases.
The Australian Government funds research indirectly via tax breaks for donors to endorsed organisations (charities) such as the HSP Research Foundation (HSPRF). It also provides funds directly to those health research Universities and other research institutions who successfully apply for funding to the NH&MRC, the Government owned National Health and Medical Research Corporation.
The other major impetus for research into rare diseases comes from support organisations such as the HSPRF. We seek funds from within our own ranks – friends & family, business contacts and corporations to fund research specifically on HSP. The goals we have established and met to date are “affordable and local gene testing” (February 2008) and a “stem cell pilot study as a first step towards a possible cure“ (September 2008). We aim to be “consistent with and additive to the research direction of our counterpart organisations globally”. Over time dialogue has been established with our global counterparts, leading to the identification of common goals and collaboration towards their achievement.
Progress and Direction
Gene silencing technology is of interest to several biotechnology companies. There is a company working on Huntington’s Disease and another on Parkinson’s Disease using gene silencing technology and success with this work will offer spin off opportunities to HSP. Another interesting genetic based technology is gene editing which harnesses the body’s own resources to repair genetic faults. It is being trialled for the “bubble boy” disease.
An American company, PTC Therapeutics of New Jersey, is in human subject trials with the drug PTC 124 , now known as Ataluren. This work is largely funded by the Muscular Dystrophy Association. The drug is showing promise for a nonsense mutation in boys with Duchenne MD. This may also hold promise for HSPers with a nonsense mutation and, given PTC is in advanced trial stage, the opportunity may be only a few years away. A gene test will answer the question “Do I have a nonsense mutation?” The probability of an HSPer having a nonsense mutation is around 10%.
Much of the medical and ethical debate around the use of stem cells has become irrelevant as cloning embryonic stem cells for therapeutic use is no longer necessary. Adult stem cells from the nose, mouth and even the skin have now been successfully grown by several researchers in different parts of the world. They are a potential avenue for gene therapy and also, as in the case of the HSPRF-funded stem cell pilot study, a method for drug discovery.
Since 2014, gene therapy/gene editing technology have advanced to the point where they have become serious candidates for investigation as potential treatments for a range of diseases, including neurodegenerative diseases.
Archive of Important HSP Research
Each quarter’s pick of HSP-related research is featured on the homepage. All research articles are archived and can be accessed at any time by clicking on the ‘Research Highlights‘ banner on the homepage.
Material for this archive has been sourced mostly from the National Center for Biotechnology Information in the USA through PubMed – a service of the National Library of Medicine and the National Institutes of Health in the USA. We are most grateful for this excellent global resource and its value to HSPers everywhere.
These articles are for information and education purposes only. Medical matters should be discussed with your doctor and specialist.