What Causes ALS? With Robert Kalb, MD

July 11, 2018 - als

Northwestern has prolonged been on a forefront of investigate a causes of amyotrophic parallel sclerosis (ALS or Lou Gehrig’s disease) and treating patients with a disease. Robert Kalb, MD, Director of a Les Turner ALS Center during Northwestern Medicine, is assured that some-more breakthroughs in a simple biology of a illness are on a approach and a heal is possible.

Photo Credit: Evangelos Kiskinis Lab, Northwestern University

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Transcript

 

Erin Spain: This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I’m Erin Spain, editor of a Breakthroughs newsletter. Amyotrophic parallel sclerosis, ALS, or Lou Gehrig’s disease, is one of a many critical of engine neuron diseases. Can swell quick with life outlook of usually 3 to 5 years after diagnosis. There’s a clarity of coercion here during Northwestern to study, improved know and yield this illness with a new expertise member heading a way.

Robert Kalb: I’m Robert Kalb. I’m a highbrow of neurology during Northwestern University Feinberg School of Medicine. I’m a multiplication arch for neuromuscular medicine and a executive of a Les Turner ALS Center.

Erin Spain: Let’s speak a small bit about ALS. Can we report a chairman with ALS and how do we diagnose them?

Robert Kalb: ALS or amyotrophic parallel sclerosis is a degenerative disorder, neuromuscular commotion where patients spin gradually weak, and it’s due to a resourceful detriment of engine neurons and a neurons that indoctrinate a engine neurons what to do. So there’s an top engine neuron, that’s a instructor, and a revoke engine neuron, that is connected to flesh cells, in both of those haughtiness cells are exposed in this illness and gradually die, heading to on-going weakness. Typically a means of genocide is due to inability to get adequate oxygen in, since respirating is marred too. It’s partial of a family of neurodegenerative diseases, that includes Alzheimer’s illness or Parkinson’s illness or Huntington’s disease. Those are all adult conflict haughtiness dungeon disorders. What distinguishes them is that a race of haughtiness cells that die is specific for any of these disorders. Although we are training that there’s a lot of overlie between them. So there are patients that have ALS that will infrequently have parkinsonian facilities or people that have a form of insanity called frontotemporal dementia, that looks like Alzheimer’s disease, though it’s indeed not accurately a same. And some of those people with frontaltemporal insanity will also have ALS. So that we consider that as we’ve gotten improved during gripping people alive over longer durations of time since of improved and improved interventions that we’re seeing, that these diseases, a borders between these diseases, are mostly blurred.

Erin Spain: When somebody comes to Northwestern and they come to a ALS, a Les Turner ALS Center, what happens next?

Robert Kalb: So ALS is a clinical diagnosis. There is no test, there’s no blood test. There is no imaging tests. There’s no electrophysiologic exam that creates a diagnosis. It’s a constellation of signs and symptoms. The constellation of issues that a studious will describe, we know, we don’t feel right or this isn’t right, we can’t do x, y, and z. It’s a multiple of those symptoms and signs, these arrange of things that a neurologist when examining a studious will say, oh, good this isn’t right, or there are there are no feeling symptoms and so a diagnosis of ALS is finished by incompatible other causes and convention all a contribution together in one unit. Typically patients will initial see their ubiquitous practitioner and saying, we know, maybe my, my palm isn’t functioning good or we can’t travel correctly, or I’m carrying problem articulating my debate or swallowing. Often what happens is a chairman is referred to, a neurologist, decides that these symptoms go in a neurological sphere. Virtually all neurologists will be means to make a diagnosis of ALS, though since it’s a comparatively singular disease, you, clinically a practitioner might usually see one studious once each 10 years. And so they, they, they wish to be certain before assigning this horrible diagnosis that a diagnosis is correct. And afterwards during that indicate they mostly get referred to a some-more specialized place like Northwestern. And we know, we have a hospital that has hundreds of patients with ALS during any one time. Many, many physicians who are utterly gifted in diagnosis, diagnosing and doing ALS. You know, once a chairman gets to a hospital and we arrange all of a pieces of information and embody a certain and a disastrous results, we’re flattering assured that, that a chairman will, we know, if a chairman has ALS that we can give them that diagnosis. And afterwards once they are enrolled in a ALS clinic, they can get a accumulation of services and support by a Les Turner Center. So this is a gift that supports patient’s caring as good as a simple scholarship research. And a indication is what’s famous as a multidisciplinary clinic, so a studious will see an ALS, a neurologist, and also maybe a pulmonary alloy and afterwards a earthy therapist and an occupational therapist and a debate therapist and in nourishment during an particular with a specialty in nutrition, since this is critical in disease. Devices, communication, amicable work, psych assistance, we know, these are, we confederate all of these services to make a peculiarity of life a best that we presumably can. And, and we consider that, it’s a prolonged day, though it’s a unequivocally cultivatable day for a patients since they get a lot out of it. And afterwards there are home services that are also supposing by a Les Turner Center. Visits, we know, does a chairman need a ramp? I’m removing adult and down a stairs. These are all partial of this extensive multidisciplinary use that we provide.

Erin Spain: How do we yield someone? What are a stream treatments out there that can possibly lengthen life or boost a peculiarity of life?

Robert Kalb: The good news is that we’ve schooled many some-more about a illness over a past decades. We’re unequivocally good during expecting what patients’ needs are, for inclination to assistance people pierce around and to pierce safely and to make certain that food goes down a right pipe. There are respirating support devices. we consider that they’ve finished good things and improving peculiarity of life, though we don’t consider that we have unequivocally finished a elemental change in a arc of disease. we consider that fundamentally for a infancy of people who have ALS, it means they have 3 to 5 years from a conflict of diagnosis until death.

Erin Spain: And that’s since investigate is so important.

Robert Kalb: Right, a pivotal here is to know a underlying simple biology that’s going wrong in engine neurons and cells that are ancillary them and intervene. we consider that we’re in a improved place now than we’ve ever been. we meant it’s an impossibly sparkling time for simple scholarship investigate and also for translating those simple scholarship observations into new therapies.

Erin Spain: You are unequivocally assured that there will be a heal or a unequivocally effective diagnosis for ALS. Maybe there’ll be something new as shortly as in 5 years. You’ve said. What creates we so optimistic?

Robert Kalb: I’m utterly certain that during some indicate there will be a pill, we take a tablet in a morning, once a day in a illness never progresses. I’m assured in that, though either that’s 6 years from now or 15 years from now, we can’t see that into a transparent round and make that prediction. However, there are other technologies, privately something called antisense oligonucleotides or ASOs that we consider are going to be fabulously absolute for a diagnosis of ALS patients. So in a beginning, what will occur is, I’m going to predict, that antisense oligos will be used to yield patients with patrimonial forms of disease. We know a mutant gene, we pattern an antisense oligos to aim that gene, to revoke a contentment of that gene. And by shortening a contentment of a poisonous gene, there should be reduction toxicity. And a reason I’m unequivocally high on this record is that there already is an instance of this working. There’s a childhood illness called spinal robust atrophy. It’s a childhood engine neuron disease. Over a past 20 years we’ve identified with a genetic monstrosity is in spinal robust atrophy. We have devised animal models of spinal robust atrophy. We have devised antisense oligonucleotides, that corrected in animal models. We have given it to tellurian beings and it has had a elemental change in a march of SMA in children. We are fundamentally restorative or carrying a outrageous impact on children and infants with spinal robust atrophy. So this is a template. This is a pathway we know works. Identify a mutant gene, digest therapies that are used antisense oligos, give them to patients. The patients will get better. So with that pathway forward of me, we consider that it’s overwhelmingly expected that antisense oligos technologies will spin out to be useful for patients with ALS in a beginning, a low unresolved fruit will be people with patrimonial forms of disease, though we consider as we learn some-more and some-more about a simple biology and we’re looking for targets in my lab that are not familial, that we will be means to aim them with antisense oligos. So I’m unequivocally high on that technology.

Erin Spain: That story can gave me goosebumps. Where are they doing that? I’m only extraordinary now, where are they doing that investigate with a children?

Robert Kalb: Nancy Kuntz and Vamshi Rao have been vital players in a SMA world. This has been happening, so this is an. This is a good story. This is unequivocally an implausible success story and we consider that neurologists, pediatric neurologists, are jumping adult and down in fad with this, we know, going from a gene to an effective therapy.

Erin Spain: This is duty during Lurie Children’s?

Robert Kalb: It’s indeed duty in many centers, though we. So Luire has been a vital actor in this margin and let me also contend that we now have teenagers and immature adults with spinal robust atrophy, that we are treating in a hospital with these antisense oligonucleotides. We have some-more than 25 teenagers and immature adults who have a milder form of spinal robust atrophy and we are administering antisense oligonucleotides to them and they tell us that they’re feeling stronger.  we mean, it’s incredible. It’s positively incredible. So, we see this as a unequivocally reasonable trail are there going to be bumps along a road? Of march there are. Will other technologies addition antisense oligos? Probably. Maybe who knows? CRISPR/Cas9, who knows? But though there’s a transparent pathway here and that’s since we consider that we’re going to have effective therapies in a comparatively nearby future.

Erin Spain: Just tell me a small bit about where your research, how distant it’s come in a past several decades and where you’re during right now.

Robert Kalb: Let’s only start by observant that many of many people who have ALS occasionally form of disease, that means that there’s no transparent genetic means and about 10 or 15 percent, there’s a transparent singular gene that is deteriorated that causes a illness and we can lane it by a family, so all of a models of disease, so we need to, if you’re going to investigate a illness in a rodent or a rodent or in hankie enlightenment or any of a accumulation of other tools, genetically manipulate organisms, we have to emanate that indication by utilizing a gene that was poor in a patients with patrimonial disease. So all of a models are formed on patrimonial disease. We use fundamentally 3 opposite platforms. We use this indication mammal called C.elegans, caenorhabditis elegans. It’s a teeny weeny small worm that lives in a soil. By a way, 6 Nobel prizes have been awarded for work regulating C.elegans. 

Erin Spain: That’s unequivocally special worm.

Robert Kalb: We also use a primary neuron hankie enlightenment models, that haughtiness cells that are subsequent from a spinal cords of mice or rats. And we also do some studies with mice too. As we could imagine, what we can do in a genetically manipulatable complement happens much, many quicker than what happens with a mice. we consider that looking during a genes that when deteriorated means patrimonial ALS, points to a several opposite dungeon biological processes that are expected to have left badly in a studious cells, we consider a vital problem is a doing of misfolded proteins. My viewpoint on this is that proteins or are a workhorse of a cell. They are a things that they are a molecules that do all a work in a dungeon or many aspects of dungeon biology and they’re constantly being synthesized and constantly being degraded. And during any one time there’s an volume of a protein in a cell, though that volume is regulated by how many new copies of a proteins are being finished and how quick that protein is being degraded. And only like a automobile wears out over time, a protein or a partial of a automobile will wear out over time, due to use, a protein, will amass repairs or will not duty as good over time. And so a reason to get absolved of proteins, to reduce afterwards is to keep them fresh, to keep, we know, a battery’s totally powered and a cylinders good and clean.  We consider that a vital problem in ALS is a approval of shop-worn proteins and ordering of them. And since this ordering routine or a approval and a ordering routine is impaired, what ends adult duty is an accumulation of shop-worn proteins and cells don’t like that. Cells are unequivocally unfortunate when misfolded shop-worn proteins accumulate. And this is indeed a common thesis for all neurodegenerative diseases and indeed many diseases that even don’t engage a shaken system. It’s a accumulation of misfolded shop-worn proteins. And so a partial of a investigate in my lab focuses on how these proteins are recognized,  how they are brought to a ordering section cells have a rabble ordering units and if any of those genes that we have found could spin drug targets. If we could promote a approval and plunge of a protein and that approval routine could be drugged, if we could make a drug that would accelerate that process, we consider that that’s gonna be an event for treating patients. And so we’re unequivocally actively concerned in those aspects.

Erin Spain: We have several labs here that are partial of a center. They’re all arrange of operative on opposite aspects of ALS. Tell me a small bit about a folks that we have right now in a core of these investigators and what they’re operative on. Some sparkling things they’re operative on.

Robert Kalb: I’ll start with a many youth and go to a many senior. So Evangelos Kiskinis Kiskinis is an partner highbrow in a Department of Neurology. He is unequivocally meddlesome in regulating models of ALS that are formed on tellurian cells. So there’s a record for holding tellurian skin cells and branch them into tellurian engine neurons and flourishing them in a plate and afterwards interrogating what they’re doing rightly from a dungeon biological viewpoint and what’s going awry. And so Evangelos is unequivocally a celebrity in a margin of this, what’s famous as prompted pluripotent branch dungeon subsequent engine neurons. And uh, he’s been upheld by a Les Turner Foundation and he only got a vital NIH grant. So we know, he’s a budding luminary if he’s not a luminary already. Hande Ozdinler is a small bit some-more senior. She studies top engine neuron. So as we said, a illness is a illness of a authority neurons or a top engine neurons as good as a revoke engine neurons. And she has devised some impossibly crafty a rodent models for looking during top engine neuron disease. And what are a determinants of presence of those selves. There’s another questioner Han-Xiang Deng who is arrange of partially eccentric of another lab. He’s finished some unequivocally impossibly fanciful work identifying new genes that means ALS and creation rodent models of them. And partial of that, as partial of a partnership with a some-more comparison investigator, Dr Teepu Siddique, Siddique is been during Northwestern for decades. He was partial of a group that found a strange gene, a initial gene that when deteriorated causes patrimonial ALS mutations in a gene called SOD, sod. Dr. Siddique is actively concerned in both a animal turn and some-more molecular biological aspects of engine neuron disease.

Erin Spain: You pronounced before that we like tough problems to solve. You’re a bit of a, indeed saw we doing a New York Times crossword nonplus when we was walking in here. Has that always been a celebrity trait for you, arrange of a nonplus solver perplexing to solve tough problems?

Robert Kalb: we like being Sherlock Holmes. we like a tough puzzle. we like to get a positive, a certain feedback when we put a final word in a crossword nonplus too, and we’re not finished there with ALS. But also we consider we need to, we demeanour during as a marathon, we need to go prolonged here. If it was easy, we would already have a answer. If there was an apparent thing, we would already have a answer and we don’t, and that only speaks of a impossibly complex, a implausible complexity of cells and in this weird way, they’re unequivocally pleasing in there. we meant they do all sorts of unequivocally implausible things, though you’ve got to commend that there they’ve had billions of years of expansion to spin unequivocally good during what they do and we’ve only now carrying all a impossibly absolute collection to puncture inside and find out what’s going on. And we am committed, we think, we consider everybody in a hospital or a physicians, Senda Driss and Mike Li and Teepu Siddique and myself and Robert Sufit, we consider we’re all unequivocally committed to holding caring of a patients and going prolonged unresolved in there and eagerness to see it by to a finish and that’s my idea is to get to a end, to put myself out of business.

Erin Spain: To find out some-more about Dr. Kalb’s research, check out a latest emanate of Northwestern Medicine repository and Breakthroughs. I’m Erin Spain. Thanks for listening.

 

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