2 Burst results for "Severe Sickle Cell Disease"
"severe sickle cell disease" Discussed on The Readout Loud
"Obviously these chemotherapy agents have been used in patients who have had some type of cancer previously so these minor toxic agents not just beautiful fan but other milo toxic agents such as taiyo tampa mel philan- etc class of that we call alka liters. They are known to be associated with occurrence of cancer in these patients. Many years down the line and as far as the hamada boyd cancers are concerned myeloid neoplasms such as am l. and md are the most common occurrence. So when you sit down with your patients with sickle cell disease to discuss potentially curative. Jennifer therapy was the reaction to the need for yourself and bone marrow conditioning. To be honest with you. It is a challenge for many patients to grasp that because first of all. They're not prepared to are. They don't even know that they are going to receive chemotherapy in order to undergo gene therapy or transplant. There is very little information out there and quite frankly a lot of misinformation out there about transplant. Angie therapy man. How these treatments work and so i always tried to make sure that all my patients understand completely. What the risks are i. Try not to give them percentages. Because you know to say something like there's a twenty percent risk of x. y. and z. is is not appropriate in my opinion because when it happens to that patient for that patient twenty percent risk doesn't mean anything for them. It's one hundred percent or zero percent right. And so i tried to tell them what's common what's going to happen. What might happen. And what's unlikely to happen. And at the same time. I try to help them understand these rats and balanced them with the risks associated with their underlined sickle cell disease. Many patients who are choosing to undergo either transplant gene therapy. Currently they obviously have severe sickle cell disease to begin with so sickle cell. Disease is a pretty bad disease which reduces the life expectancy by almost half. But when i'm talking to a patient who is in their teenagers are early twenty s. It's very difficult for them to grasp that. And that's what i envision. And i tried to do in in multiple meetings when i'm discussing either. Gene therapy transplant for them. So that the on me look at the acute toxicity and the effects of chemotherapy. But also the long term picture of what might happen. If the choose not undergo transplantation especially if they already have a very severe sickle cell disease. So you've been following the efforts to develop safer drugs than than beautiful fan for bone marrow conditioning. How far along are these research programmes. And is there anything to your mind. The teams particularly promising. There are at least three agents which i believe are quite far advanced and their clinical or preclinical development. So one agent. That i have seen which seems to be quite promising. Are cd forty five. Antibodies which are labeled with the radioactive antigen There is a trial which has ongoing currently called the sierra trial which enrolls patients were aml an md s. It's restricted to adult patients right now. Who are unable to tolerate. Chemotherapy prior to transplant and in that trial the cd forty five labeled to radio. Iodine has bruin to be a much safer alternative and much effective alternative honestly compared to chemotherapy drugs which certain older patients are. Frankly unable to tolerate another agent which we have recently learned about as a secret antibody which has been used in patients with severe combined immunodeficiency. It's a naked antibody. Secret as an antigen which is present on hemorrhoids stem cells. It's been used in patients with in a clinical trial with patients with severe combined immunodeficiency out of stanford and the results honestly in those patients have been quite promising and those are pediatric patients. I must point. Magenta therapeutics has another drug that they are currently developing a which has the same secret antibody combined to a cytotoxic. There was data presented by dr john dimsdale at believe last year's ash conference where he showed in to monkeys. They use this antibody and it was able to completely deplete their Stem cells and then they were able to rescue that by giving them autologous. John modified stem cells. So you mentioned earlier that you know when you when you talk about these bone marrow conditioning processes you know both shelves and the side effects there you have to balance that with the fact that these patients have severe sickle cell disease and there's obviously risks associated with that. But i wonder if you look ahead to a point where maybe gene therapy for sickle. Cell disease is approved And does require bom conditioning with fan at least initially like how widespread of acceptance do you think you'll see this gene therapy in the sickle cell patient community. Yeah adam that's a very difficult question to answer. But i think we have to assume that exposure to fan. You know whether it is related as it pertains to developing second cancers or as it pertains to all these other side effects including infertility which is a major concern for patients undergoing curative therapies for sickle cell. Disease i think it does make a huge impact and it does in some way reduced acceptance of these knowledge curative therapies to only a few patients who are obviously seeing an impending mortality risk to them. Obviously every therapy has its on side effects but if it can sure that the side effects associated gene therapy and the conditioning that requires are obviously less than the side effects associated with the disease itself in the long term in the next twenty to forty years. I think that's what's it finally going to lead to a widespread acceptance of these gene therapies at least in the developed countries sharma. Thanks for joining us. Thank you so much and thank you for having me turn. Venture capitalists are.
"severe sickle cell disease" Discussed on The Readout Loud
"Two thousand eighteen and a refocusing attention on whether there's a causal link with bluebirds gene therapy while bluebird investigates there's rising concern that these cancer cases could have a broader impact across the gene therapy field. We're going to discuss some of the implications of that and one under appreciated aspect of gene therapy with an expert later on in the show but before we do adam. Can you tell us what we know. So far about any link between bluebirds gene therapy and these cases of cancer. Yeah you know. We don't have much definitive information right now. Because bluebird has only learned about the two new cancer cases and is still investigating them. But here's what we do know. So one person who received bluebirds gene therapy five years ago and again. This person received that gene therapy because he had sickle cell disease up but that patient was recently diagnosed with a form of leukemia. Now the second case involved a person who received bluebird therapy more recently but then rather quickly was diagnosed with mild as plastic syndrome or md s. And that's a cancer like disease. That could also progress to leukemia now. According to bloomberg there is no definitive evidence collected yet which points to its gene therapy as the cause of these cancers but at the same time the company can't disprove that link So now it's clinical. Trials have been suspended so maybe just step back for a moment and explain at least theoretically how gene therapy might cause cancer so let's step back even further and kind of go over what gene therapy is right. Gene therapy is a procedure in which a damaged disease causing gene is replaced with a healthy gene. That functioned normally now to do that. They use viruses. These viruses are engineered to be harmless. And they're used to deliver the healthy genetic material inpatients because viruses are very adept at infiltrating cells. Now however if that virus shuttles that genetic material into the wrong place. On a patient's chromosomes it could for instance switch on cancer causing gene or it could disable a gene that prevents cells from turning into cancer so the cancer risk associated with gene. Therapy is really small but still it's enough that companies put in place safety checks to make sure that these viruses don't miss the liver that genetic payload and still the these safeguards how are like. They're just not foolproof. So figuring out the root cause of these cancer cases we talked about is obviously deeply important. For bluebird in the short term but as mentioned earlier there are potential repercussions for the entire gene. Therapy field right. Yeah that's damian. So this bluebird gene therapy uses a particular type of viruses called a lengthy virus to deliver those healthy genes into patients. Now lentiviruses are particularly adept at integrating into the genome of target cells. Which makes them effective delivery vehicles for gene therapies that target cells that divide or turnover rapidly. So that's true with sickle cell disease for instance which involves red blood cells Now if these lundy viruses are found to carry an unacceptably high cancer risk you know. That's obviously a big problem. For bluebird but also for a host of the other companies that are developing gene. Therapies that utilize lenny viruses as delivery vehicles. So we should note that. It's entirely possible that these cases of cancer have nothing to do with the lenghty virus component of bluebirds gene therapy. And a rather stu random chance however it's also possible that the culprit is a decades old. Chemotherapy called butyl fan. That is used to prepare patients. For gene therapy. This is one of the more underappreciated in less discuss aspects of gene therapy so to help us understand what's going on with the situation. We're joined by dr shave. Sharma a bone marrow transplant expert at saint jude children's research hospital. Welcome to the podcast. Thank you so much damian and thank you for the opportunity to speak to all of you today. we'll maybe let's start with your thoughts on kind of the situation overall. When you saw the news what do you think might be going on. Here honestly was a shock to many in the community both providers what taking care of patients as well as the patients Off spectacle cell disease. Something that we all need to be aware of and should be obviously looking out for is that there may be multiple mechanisms which are involved are multiple risk factors which may be involved. I am aware that many in the field and lay public are definitely concerned that this could be related to lend viral vectors as we just talked about that is obviously a factor that is under investigation and a point of concern but lengthy viral vectors. Not unique to sickle cell gene therapy lengthy viral vectors off. Some kind have been used in over ma many hundred patients so far for multiple diseases. So that's one aspect that needs to be investigated but many people don't know that sickle cell disease by itself is a myeloid leukemia. predisposition syndrome. There was a study published a couple of years ago from california where they found that the risk of myeloid malignancies in patients with sickle cell disease was very high in fact it was almost four times higher than the general population and patients of had severe sickle cell disease. And then of course. There is the question of exposure to milo toxic agents such as butyl fan which was discovered to be the case in the previous patient that was described almost two years ago so i wanted to zoom in on the fan aspect in particular. I think people might be surprised to learn that. Chemotherapy is a necessary step in the gene therapy treatment process. These patients are seeking treatment for an inherited disease like sickle cell disease. They don't have cancer. So why are they. Getting chemotherapy damian. That's a very good question in fact that's something that i'm asked all the time. When i i meet with patients who are want to undergo either transplant gene therapy. You know people normally assume that. Chemotherapy is only used to treat cancer. But that's not absolutely true. We do use milo toxic. Our agents are drugs which are which stem cells in order to create space in the bone marrow so that then we can put new stem cells. Either from somebody else as happens in the case of aboard marrow transplant or genetically modified stem cells from the patients themselves. Back into their bone marrow. So right now. Chemotherapy is an essential part of just gene therapy. But all types of transplants that we are doing for inherited disorders of the hemorrhoids system. Not just tickled disease. But palestinia certain bone marrow failure syndromes immunodeficiencies et cetera. Is there an established link between the use of fan and an increase risk with so-called secondary cancers even even years later so we know from you know giving chemotherapy to patients Over the last several years that data is a data connection of some milo toxic agents and development of second cancers down the line what i mean by second cancer as most of the times..