Latest / EHA Unplugged / Gene Therapy Advances in SCD and B-Thalassemia (with Dr Stefano Rivella)

Transcript

Gene Therapy Advances in SCD and B-Thalassemia (with Dr Stefano Rivella) · EHA Unplugged

• 0:03
  Greetings and welcome to EHA Unplug, the official podcast
• 0:06
  channel of the European Hematology Association, EHA.
• 0:10
  Hello, I am Isabella Libera, a medical writer for EHA.
• 0:15
  Welcome to our podcast exploring the recent gene therapies
• 0:20
  approved for sickle cell disease and transfusion dependent Vita
• 0:24
  thalassemia. Today, we are thrilled to have
• 0:27
  here Doctor Stefano Ribella, a hematologist and research
• 0:32
  faculty member in the Division of Hematology at Children's
• 0:35
  Hospital in Philadelphia. Welcome, Doctor Vela.
• 0:40
  Thank you so much for inviting me.
• 0:42
  It's an honor for me to, you know, address these questions
• 0:46
  about gene therapy. I'm Stefano Rivella.
• 0:50
  I was born in Italy and moved to United States when I started my
• 0:54
  post doctoral work. I was always very interested in
• 0:58
  doing gene therapy because during my work in Italy, I I was
• 1:04
  basically basically cloning genes and try to identify genes
• 1:07
  that are associated with mutation, etcetera.
• 1:10
  But I thought the future of medicine was going to be used as
• 1:13
  information to cure patients. So I moved to United States.
• 1:16
  I start working on gene therapy when a lot of people didn't
• 1:20
  think it was an interesting topic and now it's history.
• 1:23
  We have a lot of products that we can discuss about and patient
• 1:26
  and being treated with this Novo technologies.
• 1:30
  Thank you for being with us today.
• 1:33
  So we want to explore in this podcast how this recent gene
• 1:37
  therapies for sickle cell disease and beta thalassemia
• 1:40
  work, their clinical safety and efficacy and how would this
• 1:45
  widespread their use is or will be.
• 1:50
  So let's start by the basics. What gene is there to repair?
• 1:56
  What it mean is what is the molecular defect in sickle cell
• 2:00
  disease and in beta thalassemia? Sure.
• 2:04
  So beta thalassemia and sickle cell anemia are basically sister
• 2:08
  diseases in the sense that in sickle cell anemia were a single
• 2:13
  mutation in the gene called beta globin.
• 2:16
  And this mutation basically modifies the structure of the
• 2:19
  protein, which is an important element to make hemoglobin.
• 2:24
  So hemoglobin is oxygen, oxygen carry a molecule that presents
• 2:27
  all our red cells. And without that we don't
• 2:31
  transfer oxygen from the lung to the, you know, to the many cells
• 2:34
  in our in our organ in organs. And so the sickle cell mutation
• 2:40
  modified the structure of the beta globin gene in beta
• 2:43
  thalassemia. The the gene is the same, the
• 2:47
  the the mutation are wherever different in the sense that all
• 2:51
  the mutation associated with beta thalassemia decrease the
• 2:53
  expression on the beta globin protein.
• 2:56
  So in other words, again looking at hemoglobin which is the
• 2:59
  oxygen carry molecule is made of 22 primarily by two 2 proteins.
• 3:05
  1 is called beta, one is called alpha.
• 3:07
  And so in beta thalassemia we have a product reduction, so few
• 3:12
  beta globin proteins and an excess of alpha globin proteins.
• 3:16
  And this unbalance is responsible for the toxicity of
• 3:21
  the cells. Red cells don't don't cope well
• 3:23
  with this excess of half a chains and, and they die, they
• 3:26
  don't differentiate well. They expand in the, in the bone
• 3:29
  marrow, in the spleen of the patients and and the patient in,
• 3:32
  in in both cases, sickle cell and thalassemia.
• 3:35
  Many times patient require blood transfusion like every 2-3
• 3:39
  weeks. They need to get blood from
• 3:41
  donors because they don't make red cells or they make bad red
• 3:44
  cells. And so they need those donable
• 3:47
  red cells to survive. So there are two gene therapies
• 3:54
  that have been approved by FDA for sickle cell disease and for
• 3:59
  sickle cell disease. So Lithuania and Caschevi,
• 4:02
  correct, Caschevi is also approved for transfusion
• 4:07
  dependent beta thalassemia, correct.
• 4:10
  And then in Europe only Caschevi is approved.
• 4:14
  Yes, is the situation. Yes, yes, yeah.
• 4:16
  They work in different ways, yes, yes.
• 4:18
  Can you explain briefly how Lithgenia?
• 4:21
  Works absolutely so. So the two products are
• 4:25
  different in the sense that a lithgenia works is so considered
• 4:29
  is considered a technologies called gene addition or gene
• 4:31
  complementation. So what does it mean?
• 4:34
  Means that, you know, patient has a mutation in the beta
• 4:36
  globin gene could be sickle cell or thalassemia and gene
• 4:40
  complementation of gene addition means basically they introduce
• 4:44
  in the stem cells and multiple stem cells of this patient, an
• 4:47
  additional copy of the gene that in this case that doesn't have
• 4:51
  mutation. And so would compensate for the
• 4:54
  lack of production or dilute the sickle cell protein production
• 4:58
  in the stems in from the in the retro cells that are being from
• 5:01
  the stem cells of the patient. So in order to achieve this gene
• 5:05
  addition, you need to use a tool that allows basically allows
• 5:09
  the, you know, the physician, the scientist to introduce this
• 5:12
  additional copy of the beta globin gene inside the cells.
• 5:16
  And this is mediated by done by using a viral viral vector.
• 5:20
  In this case, we use take advantage of the fat, the
• 5:22
  lentiviruses. You know, the HIV viruses was
• 5:25
  very, it was very good in infecting, infecting cells in
• 5:30
  particular in mythically stem cells.
• 5:32
  So now you have basically the envelope that looks like an HIV
• 5:37
  virus, but what is inside is the information to cure beta
• 5:41
  thalassemia sickle cell anemia. And since the information that
• 5:45
  really stays in the, in the cells after infection is
• 5:49
  basically the, the component of the makes the beta globin gene,
• 5:54
  you don't really have an infection with an, an active HIV
• 5:57
  virus. For gene editing.
• 5:59
  The, the, the, the, the technologies evolved from a
• 6:02
  different kind of, you know, from different studies, from
• 6:04
  knowledge, completely different knowledge.
• 6:06
  So this is called a CRISPR CAS 9 system.
• 6:09
  And it's basically system to allows gene editing or gene
• 6:13
  modification of the DNA of the cells.
• 6:15
  You can basically, you know, modifying the, the, the sequence
• 6:21
  of a gene, you can theoretically prevent the gene from
• 6:25
  functioning. And so they decided to to do
• 6:29
  something very smart, which was, it was basically there is a gene
• 6:33
  in, in, in all of us that makes a different kind of hemoglobin
• 6:38
  called fetal hemoglobin. So it's a kind of hemoglobin
• 6:41
  that we make when we are in neutral in, you know, in the
• 6:43
  womb of our, you know, matters. But then after birth there is a
• 6:47
  switching. So basically that gene that
• 6:49
  makes fetal hemoglobin is basically turn off while the
• 6:54
  gene that makes adult hemoglobin as a beta globin gene is turned
• 6:57
  on. And so people say what if we
• 7:01
  basically impatient have sickle cell anemia and thalassemia, we
• 7:05
  can reverse the reverse that process.
• 7:07
  So now we basically I reactivate the fetal hemoglobin gene,
• 7:12
  right? And, and automatically the
• 7:14
  expectation that the adult hemoglobin gene, the mutant, the
• 7:18
  mutated beta globin gene will be stuck, will be, you know, switch
• 7:22
  switched off. And so people start thinking, so
• 7:26
  this is possible, right? There is a fetal hemoglobin gene
• 7:29
  available. Normally we don't use it and
• 7:31
  they're actually few people walking around.
• 7:33
  They actually, I have this persistent expression of the
• 7:37
  fetal hemoglobin gene and they're do pretty well.
• 7:40
  So people started studying, you know, by looking at, you know,
• 7:46
  studying large population and try to identify when there were
• 7:50
  higher level of fetal hemoglobin expression in those few
• 7:53
  individuals. If there was anything, any gene
• 7:57
  that could be associated with, you know, modification in this
• 7:59
  expression. And eventually they identified
• 8:02
  gene called BC11A. And so this gene is I would say
• 8:07
  today is probably the master regulator or fetal hemoglobin.
• 8:10
  Of course there are other genes that collaborate and other genes
• 8:12
  that contribute to the expression of fetal hemoglobin.
• 8:15
  But this historical has been now probably the most studied gene
• 8:20
  to the regulates fetal hemoglobin.
• 8:21
  And people realize that if you can block somehow the expression
• 8:25
  of that gene, you can reactivate fetal hemoglobin.
• 8:28
  So Khazjabi, the product made by Khazjabi is basically taking the
• 8:34
  the cells of the patients, introducing the CRISPR cast 9,
• 8:38
  cast 9 system and you can target specific sequence in the DNA of
• 8:42
  the patient and in this case the regions of the gene BC11A that
• 8:48
  are important for this expression.
• 8:50
  And if you target those sequences, you can basically
• 8:52
  block the expression of the gene.
• 8:54
  And when the gene, the expression of the gene goes
• 8:57
  down, then fetal hemoglobin gene goes up.
• 9:00
  I will have one question first for Lithuania.
• 9:03
  So as you explained, it's a gene addition.
• 9:08
  So this happens randomly in the genome, correct?
• 9:12
  So it could be inserted in a place that is, you know that
• 9:19
  they use for for the cell and also it could be many copies
• 9:23
  that are inserted. How right have you seen?
• 9:29
  So the two system are, I would say still in their infancy and
• 9:32
  we need to be aware there are limitations to to these
• 9:37
  approaches. So if we focus on gene addition,
• 9:40
  it's true what you're saying the the integration of this gene as
• 9:44
  with the current technology, it's pretty random.
• 9:46
  It's not completely random. You know people study and they
• 9:50
  realize that you know there are specific region in the gene on
• 9:53
  there at least in the matter by the stem cells that being a good
• 9:57
  target for this you know this virus to land and introduce the
• 10:01
  gene. However, basically all the
• 10:06
  patient have been treated with this technology except for few
• 10:10
  exceptional, but all the patient are this treated for beta
• 10:14
  thalassemusicocell anemia and they never had a problem.
• 10:17
  And so even if there's a relative random integration and
• 10:20
  the number of copies can change from one patient to them to
• 10:23
  another, none of them so far developed leukemia, which is
• 10:27
  obviously one of the concern that people had at the
• 10:31
  beginning, especially because some of their initial studies
• 10:33
  were done with different kind of viruses.
• 10:36
  And now many patients have been treated and we didn't see that
• 10:39
  there've been a few things, you know, couple patient that
• 10:42
  developed level of leukemia, for instance, in in the, in the
• 10:46
  patient population treated with Genia, but they were not related
• 10:50
  to the integration of the vector.
• 10:52
  And people are still wondering why that happened.
• 10:53
  It may be that, you know, the sickle cell population may have
• 10:57
  higher level of clonidal metopoiesis because inflammatory
• 11:02
  media and background that they, they suffer all their life and
• 11:05
  that leads to, you know, an increase rate of mutation that
• 11:11
  over time may lead to may lead to leukemia.
• 11:14
  The bone marrow transplantation is something that may increase
• 11:18
  the chances of leukemia as well. And this probably if, if what
• 11:24
  I'm saying is correct, it it, it, it doesn't makes, it doesn't
• 11:28
  make any difference if you treat the cells with an antiviral
• 11:31
  vector with or with a, with a gene editing tool.
• 11:34
  Because if the patient with sickle cell anemia
• 11:38
  predisposition, I would say to acquire mutation in the stem
• 11:42
  cells as they get older. This should only be, you know,
• 11:48
  the, the, the lengthy versus the gene editing per SE approach
• 11:52
  should not differentiate between should not promote one or the
• 11:55
  other more right. However, the gene editing
• 12:00
  approach is theoretically more focused on the single, you know,
• 12:04
  single the, the fine sequence in the genome of the patients.
• 12:09
  However, there are potentially side effects.
• 12:12
  For instance, that, you know, this technology as it, as it is
• 12:15
  right now from Casgevi is basically, it's really the first
• 12:20
  technology came out when CRISPR CAS 9 was utilized for, for, you
• 12:24
  know, gene, gene gene therapy. So this is a technology
• 12:29
  basically creates a double strand cat in the DNA.
• 12:33
  So you think about a chromosome which is normally long molecule
• 12:36
  of DNA suddenly is divided in two parts and now these two
• 12:40
  person come back had to come back together, right.
• 12:44
  So and this probably happens in majority of the cases.
• 12:48
  But you can imagine now that these two you know, 2 portion of
• 12:51
  the chromosome can start like you know interacting with other
• 12:54
  region of the genome and they may create instability in the
• 12:57
  genome etcetera. So we don't know for sure if
• 13:02
  these technologies is absolutely safer than the other technology
• 13:06
  there is. There are definitely pros and
• 13:08
  cons. I think we we need to study them
• 13:12
  carefully looking at long term effects in the patients and then
• 13:17
  decide if there is really a difference or not and that
• 13:20
  eventually 1 is better than the other.
• 13:23
  We don't know what are the long term effects of expressing high
• 13:26
  level of fetal hemoglobin, right.
• 13:29
  This is something that I said there are a few people express
• 13:31
  some level of fetal hemoglobin. The benefit from having those
• 13:35
  levels instead of having full, you know, the full disease
• 13:39
  sickle cell or thalassemia. But the way we are, you know,
• 13:44
  increasing the fetal hemoglobin now is really to vary, you know,
• 13:47
  maximum or high, very high level, especially in thalassemia
• 13:50
  where there is no almost no competition or sickle cell
• 13:53
  anemia. You still you create the fetal
• 13:55
  hemoglobin, but there is still some, you know, proportional
• 13:58
  sickle which is in, you know, diluting the fetal right
• 14:03
  somehow, right or the fetal is saluting the sickle.
• 14:05
  But all together, maybe a good combination In beta thalassemia
• 14:10
  when you don't have very low level of beta globin, you're
• 14:13
  expressing majority of fetal hemoglobin.
• 14:15
  So fetal hemoglobin is a is a hemoglobin that has a higher
• 14:21
  affinity for oxygen. So in other words, you know,
• 14:24
  when you breed oxygen, the hemoglobin is capturing oxygen
• 14:28
  in your lung and as it goes around in your body.
• 14:31
  And, you know, basically lases oxygen based on the
• 14:35
  concentration oxygen that decreases as you mow from the
• 14:38
  lung to other organs. Now with fetal hemoglobin, this
• 14:43
  oxygen affinity is higher. So we don't know how is
• 14:46
  released, you know, in, in, in, in our organs and, and if there
• 14:52
  is any potential side effects in the long term.
• 14:55
  So there are a lot of things that are right now we are
• 14:59
  learning because we we never had a situation, you know, we
• 15:05
  couldn't really analyze people with this kind of in artificial
• 15:09
  way of expressing genes, right, which is curing many of them.
• 15:13
  But it's definitely almost artificial, right, in, in a way.
• 15:18
  So it's a normal technology. Why not to try to repair with
• 15:26
  crisp sure endogenous mutation? Absolutely.
• 15:28
  So the, the next step, I think what people are trying to do now
• 15:32
  instead of doing like, you know, you know, the base editor came
• 15:36
  after, right? So the base editors are now
• 15:38
  basically fused proteins. Basically the, the, the, the
• 15:43
  cast 9 now is fused with additional proteins.
• 15:47
  They have the ability now to recognize a base and modify and
• 15:54
  revert that base. That mutation, that base is
• 15:56
  considered like, you know, sickle cell anemia.
• 15:58
  There is a specific mutation. The idea is to go there and
• 16:01
  revert that mutation back to a sequence that now not harmful,
• 16:06
  right? And so this technology has
• 16:07
  considered obviously safer than just going there and opening the
• 16:12
  Chrome zoom in two parts. So there is an evolution of all
• 16:15
  these things and and should. Be particularly easy in sickle
• 16:19
  cell disease. It should be.
• 16:21
  Sickle cell. Sickle cell, right?
• 16:22
  Definitely. So there are no base editors
• 16:25
  that can revert the mutation of sickle cell mutation back to the
• 16:28
  original sequence. But people realize that there
• 16:32
  are in Indonesia that is a hemoglobin called Macassar and
• 16:37
  that hemoglobin is completely normal.
• 16:39
  And it's different from the normal hemoglobin we make, but
• 16:42
  it's different in the sequence is different amino acid.
• 16:45
  The, the, the, the amino acid sequence is different, but it
• 16:49
  works as well as the normal 1. And so the people realize that
• 16:53
  with the current base editors, we can modify that mutation and
• 16:57
  make a sickle cell mutation, transform the sickle cell gene
• 17:00
  in a Macassar gene and the Macassar gene, as I said, is is
• 17:04
  work works well. So now people are trying to do
• 17:07
  that. So instead of using again
• 17:10
  targeting the gene, opening the chromosome in two parts, they're
• 17:13
  trying to use Basiritor to modify the sickle cell mutation
• 17:16
  in a Macassar sequence. But again, technology is
• 17:21
  evolving and now basically we have, you know, potential prime
• 17:26
  editing system. Prime editing system is it's
• 17:28
  again an evolution on the CRISPR CAS 9 system.
• 17:32
  Again, it doesn't break the DNA in two parts, but is able
• 17:36
  basically to modify the sequence as you like.
• 17:40
  So then you can theoretically correct whatever mutation you
• 17:44
  want. It's not dependent on base
• 17:46
  editors anymore that are limiting what they can do.
• 17:50
  It's it's a it's a technology. It's not efficient yet as the
• 17:54
  base editor technology, but I suspect the sooner will be would
• 17:59
  be efficient enough to correct, you know, sickle sub mutation
• 18:04
  exactly as it is, as it should be and saw the mutation.
• 18:09
  But there are other technologies evolving as well.
• 18:11
  You know, there's still just, you know, the prime editing, but
• 18:13
  there are different ways to modify the, the CRISPR cast 9
• 18:17
  probably talent sequence, the talent technology, which is a
• 18:20
  basically protein that can recognize a specific sequence in
• 18:23
  the DNA can modify also to do base editing or maybe other
• 18:30
  other things that the CRISPR cast 9 system does now.
• 18:34
  So there are a lot of moving parts and, but I think the most
• 18:38
  exciting part is really moving from this kind of technology,
• 18:42
  which is called X vivo. You, you're probably familiar
• 18:45
  with that. So, so the key right now, I mean
• 18:48
  that the, the, the, the, the current approach is basically,
• 18:51
  if you want to cure a patient with gene addition, with gene
• 18:54
  editing, you basically need to take the bone marrow cells out
• 18:59
  of the patient right this now, you can do this by mobilization
• 19:05
  and basically drugs that push the cells out of the bone marrow
• 19:09
  go in circulation. And so you do something called a
• 19:11
  phrases, which means you collect the blood from these patients
• 19:15
  and then you select the stem cells are in circulation.
• 19:18
  Normally the stem cells are not in circulation, but you can give
• 19:20
  drug to the patient so that basically they go in
• 19:23
  circulation. And when you collect the cells,
• 19:26
  you put them in a Petri dish. And now you do what you want to
• 19:29
  do. You, you know, do gene transfer
• 19:31
  with the anti viral vector. You do these editing or or
• 19:35
  CRISPR cast iron, you know targeting BC11A, but then needs
• 19:40
  to put back these cells into the patient BOMAT, right.
• 19:44
  And so I would say the mobilization and the collection
• 19:47
  of cells is relatively benign for the patient.
• 19:50
  But putting back this patient, the patient in into the patient
• 19:54
  is basically requires basically meal, meal ablation and meal
• 19:59
  ablation is still a very, very toxic pass toxic procedures.
• 20:04
  So basically use chemicals that basically in order to put the
• 20:09
  cells back, you need to make space in the bone marrow.
• 20:12
  I mean, simplifying, but basically think about like, you
• 20:15
  know, the bone marrow is full of the stem cells that have the
• 20:19
  mutation and you want to put back now the stem cells that are
• 20:23
  corrected, right? But if you don't make space in
• 20:26
  the bone marrow, these stem cells will not home.
• 20:29
  You know, they will not find a place, safe place where they can
• 20:32
  basically home and then proliferate.
• 20:34
  So you need to do something called meal ablation.
• 20:36
  Meal ablation is really giving, giving, giving very toxic drugs
• 20:41
  to the patient to kill the bone marrow.
• 20:44
  But these drugs not only kill the bone marrow and one of the
• 20:48
  major side effects is most of the patient became infertile
• 20:52
  because, you know, these drugs also affect the germinal cells.
• 20:56
  And so think about a patient, you know, think about a family
• 21:00
  now they have a kid with sickle cell anemia, beta tracemia.
• 21:05
  And maybe they, you know, they do well in the sense, you know,
• 21:07
  they're treated well, they go to a good hospital.
• 21:12
  They don't really have major problems.
• 21:14
  Of course, they need to get transfused, but they, they,
• 21:17
  they're thriving, they're growing, the et cetera.
• 21:19
  And, and the patient and the parents and the, and the kid are
• 21:23
  facing this dilemma. I'm doing OK, but but I can cure
• 21:28
  my, you know, there's now gene therapy.
• 21:30
  I can theoretically cure my disease, but I basically need to
• 21:33
  go through a meal oblation. So I think this is now the, the
• 21:38
  major roadblock or you know, the major negative aspect of these
• 21:47
  technologies, right? I mean, and when I say
• 21:48
  technologies also, even allogeneic bone marrow
• 21:52
  transplant, like, you know, getting the bone marrow from a
• 21:54
  donor, which is not gene therapy per SE, it's a cellular therapy.
• 21:59
  But even in that case, you need to do meal oblation, right?
• 22:03
  And so these are really the the major, major problems.
• 22:06
  And so people, including myself are working on novel methods to
• 22:12
  do create novel meal oblative regiments are not toxic.
• 22:17
  All is known as toxic as they do one that they've given to the
• 22:21
  patient now or doing vivo gene therapy, which is basically the
• 22:25
  idea of transferring this information directly to the bone
• 22:30
  marrow cells without like taking them out, do the meal ablation
• 22:34
  and putting them back etcetera, etcetera.
• 22:36
  So if we can in a step wise fashion, maybe eliminate the
• 22:42
  meal ablative toxicity, the major meal ablative toxicity
• 22:45
  first and then eventually get to a point where we can do in vivo
• 22:49
  gene therapy that will be very, very convenient for the patient,
• 22:53
  safer and also is also cheaper. You know, on the technology to
• 22:58
  do in vivo gene therapy is pretty much the technology we're
• 23:01
  using for the COVID vaccine. So, and, and on those are
• 23:07
  relatively, you know, it's a relatively cheaper technology
• 23:11
  then you don't need to bring the patient to the hospital for a
• 23:14
  long time. It doesn't, you know, the
• 23:17
  patient doesn't became immunocompromised because you
• 23:21
  the bone marrow, the, the, you know, ablation really eliminate
• 23:24
  the, the, you know, many cells in the, the white cells,
• 23:27
  etcetera. So they'd be, you know, they're,
• 23:30
  they're prone to infection, etcetera.
• 23:32
  You know, the idea to do in the origin therapies really the the
• 23:35
  goal is to infusing to the patient with one or two
• 23:39
  injection the product that will correct the stem cells and then
• 23:43
  come to the you know, goes to the clinic, gets in fact gets in
• 23:47
  the injection and walks back the same day to go home.
• 23:51
  So this is, you think the future, that's what you're
• 23:54
  working on to develop this kind of technology, Yeah.
• 23:57
  Yeah, I was very lucky. I mean, I'm at shop at
• 24:00
  Children's Hospital Philadelphia, but also I'm a
• 24:02
  faculty at the Upenn Penn University and one of my
• 24:06
  colleague is Drew Weisman, who won the Nobel Prize for the
• 24:11
  COVID vaccine because of tremendous impact on, you know,
• 24:16
  of this technology on saving millions of life and, and, and,
• 24:20
  and simplifying also the way we can generate vaccine now.
• 24:26
  And so is technology basically is based on the fact that you
• 24:30
  can create this leaping nanoparticles, which are
• 24:32
  basically kind of like almost fat molecules, but they're made
• 24:36
  in a way that you can include inside and that inside this
• 24:39
  molecules, a piece of RNA, you know, RNA sequence, which is
• 24:44
  basically information, right? And so the original technology
• 24:49
  was basically established to deliver RNA to trigger immune
• 24:53
  response against the, you know, the, the, the, the virus, you
• 25:00
  know, COVID virus. And, and, and so a few years
• 25:05
  ago, I, I was talking to him and we've come out with the idea
• 25:08
  that maybe that technology, since we're really, what do you
• 25:12
  need to do in order to do gene editing to correct the cells is
• 25:17
  really to deliver information so that these cells can correct the
• 25:22
  correct the gene mutation, right.
• 25:24
  And so we already know that the, you know, base editor, for
• 25:27
  instance, are able to do so. And, and base editors are
• 25:31
  proteins and they're a little component of RNA, but pretty
• 25:34
  much are proteins. But proteins can be made by the
• 25:36
  cells if you deliver the RNA that contains information to
• 25:40
  make, to make the CRISPR, the base editor system, right?
• 25:45
  So we, we discuss and how can we make the system expand this
• 25:49
  technology from doing vaccine to, to, to deliver inside the
• 25:55
  cells information that can terrifically correct the cells,
• 25:59
  right? And so we, we, so in, in the
• 26:02
  case of the vaccine, you inject, you know, your LMP lipid
• 26:05
  nanoparticles with RNA, it's an injection in your muscle and
• 26:10
  that's where you basically create the immune response, I
• 26:12
  guess a specific portion of the virus.
• 26:16
  In our case, we wanted to get to the bone marrow.
• 26:18
  And so first of all, you don't inject, you know, if you inject
• 26:21
  that in the, in the muscle would not, it wouldn't go in the right
• 26:25
  place. So you need to inject this in
• 26:26
  the blood like in you know, so they can go in circulation.
• 26:30
  But after this leaping nanoparticle going circulation,
• 26:34
  how do they know they need to transfer the information to the
• 26:36
  bone marrow and not to another organs, right?
• 26:39
  And so we decided to modify this leaping nanoparticles, what
• 26:44
  something I call Agps information, which basically is
• 26:47
  an antibody that was basically situated on the surface of the
• 26:55
  small, this leaping nanoparticles.
• 26:56
  And this antibody has the function to recognize a specific
• 27:01
  receptor, which is present in stem cells.
• 27:04
  And so these molecules go in circulation, but they don't
• 27:08
  necessarily stop everywhere, right?
• 27:10
  They just stop when they see there is a signal to tell them
• 27:14
  that's the right place. And so using this technology,
• 27:18
  we, we published A manuscript last year showing that's
• 27:22
  possible. Of course, we are talking about,
• 27:24
  you know, mice and not humans yet, but that really opened the
• 27:29
  gate to many, many investigation.
• 27:32
  I mean, I, you can, I think all the major biotechs are now
• 27:37
  investing in this technology because as, as a potential to be
• 27:42
  curative not just for sickle cell disease, but for many, for
• 27:45
  many, many diseases. And if you don't target a stem
• 27:48
  cell, you target the liver, you target other organs.
• 27:51
  You can now imagine how can you really correct many, many
• 27:55
  diseases. So you did say that access is a
• 27:59
  big issue because the price at the moment of this gene
• 28:02
  therapies is really high. So you are now working on
• 28:07
  solutions to this. But for the moment, how many
• 28:13
  patients have received this therapy?
• 28:16
  Well, I would say probably in a couple of hundreds patient or
• 28:21
  even more, but I completely agree with you.
• 28:24
  It's a very expensive, it's a very expensive drug, right?
• 28:28
  Because it's not just a drug. It's not like a, when you
• 28:32
  generate this drug, it's not like a pill and then you give it
• 28:35
  to the patient. It's a procedure, right?
• 28:38
  So you need to make the virus or you need to make the ingredients
• 28:41
  to do the CRISPR CAS 9. Then you need to bring to the
• 28:44
  patient, the patient the first time in the hospital to collect
• 28:46
  the bone marrow cells. Then you treat this bone marrow
• 28:49
  cells by 1 system or the other. And then you check if the stem
• 28:55
  cells are still stem cells if they're they were treated well,
• 29:00
  if they don't, they're using a in a contaminated stem cells,
• 29:04
  right? And all you do all this testing
• 29:07
  and then when the cells, stem cells are ready, you bring the
• 29:10
  patient back, you do the meal ablation and then infuse the
• 29:13
  stem cells. But then you need to wait a few
• 29:15
  weeks, several weeks, because after meal ablation, patient is
• 29:19
  immuno incompetent, right? So it can get an infection that
• 29:24
  can theoretically be lethal. And so you need to keep this
• 29:26
  patient in the hospital for several weeks.
• 29:29
  So you can imagine, now we have several steps, right?
• 29:32
  So we need to make a virus. We need to be, you know,
• 29:35
  so-called GMP grade good manufacturing practice
• 29:40
  technology need to be used to make this virus so that can be
• 29:42
  used in patient and not like, you know, I make the virus in
• 29:45
  the lab to for mice. And you know, obviously it's
• 29:47
  challenging, but it's not as expensive and you know, it
• 29:51
  doesn't require that level of production that you, you is
• 29:56
  required for treating humans. And, and then there are all
• 30:00
  these additional procedures. So all together the product can
• 30:04
  be in the, in the, in the range of two $3,000,000 per patient
• 30:08
  plus the expenses at the hospital, etcetera.
• 30:12
  So how do we fix this problem, right, Because it's it's it's a
• 30:18
  problem here in United States, it's a problem in Europe, even
• 30:21
  if we are relatively in countries that can afford to pay
• 30:24
  some of this cost. Bastille is very high and not
• 30:30
  all the patient, especially in places where you know, countries
• 30:35
  cannot afford that. All insurance don't afford don't
• 30:38
  allow the patient to get the therapy.
• 30:40
  Especially that this sickle cell disease and thyrsemia are more
• 30:44
  prevalent in countries. That are exactly so, yeah.
• 30:47
  Income or low income? Exactly.
• 30:49
  I was getting there because if you can imagine how difficult is
• 30:52
  maybe here, it's impossible in a country where there is no way
• 30:56
  they can spend two $3,000,000 to treat the patient.
• 30:59
  Despite the fact the majority of the patient with sickos and
• 31:01
  anemia and thalassemia are not in United States, are not in
• 31:04
  Europe and in, in, in countries that cannot afford these
• 31:09
  therapies, right. So we need to start thinking
• 31:12
  about a different way to, to develop these therapies and how
• 31:19
  to distribute them. I have number of ideas.
• 31:26
  I hope 1, you know, help one of them will be implemented by
• 31:29
  someone has the power to do that.
• 31:30
  I am no companies and I'm making this as a as a scientist and
• 31:35
  then people use this information to make drugs, etcetera.
• 31:39
  But if I were if I had a company myself, first of all, you know,
• 31:47
  depends on the technology because it's vivo and X vivo.
• 31:50
  They're two different kind of technology, but let's focus on X
• 31:53
  vivo. So first of all, I would, I
• 31:56
  would say, well, we've you know, intellectual property on this.
• 32:00
  You know, I'm speaking as I'm the owner of the company, right?
• 32:03
  We have an intellectual property about these.
• 32:06
  First of all, how do we make this cheaper for the patients
• 32:09
  here? But the other thing I would do,
• 32:11
  I would say, let's talk with those countries where bringing
• 32:16
  the product that would be too expensive and I would give my IP
• 32:20
  to them. They would invest in facilities
• 32:24
  to make this, you know, products like a maybe a nonprofit
• 32:30
  organization, nonprofit company. And, and, and I would try to
• 32:35
  teach them to do it with help from organization that are want
• 32:40
  to bring this therapist to the patients and help them or help
• 32:43
  me also. And then I will say, OK, let's
• 32:47
  teach them how to do it in in their place, having the facility
• 32:50
  to do it. That will be cheaper, right?
• 32:53
  And then I'll provide this product to the patients.
• 32:55
  This actually is happening with vaccine.
• 32:58
  Now Drew Wiseman is actually doing this.
• 33:00
  It's basically helping for countries that otherwise
• 33:04
  wouldn't be, wouldn't be able to buy even the vaccine to create
• 33:07
  GMP facility in those countries. It talk with companies and the
• 33:11
  companies are help basically to transfer the technology to those
• 33:19
  countries where they wouldn't, they wouldn't be able to sell
• 33:23
  the vaccine anyway because they they, you know, those people
• 33:25
  wouldn't have the money to buy from them.
• 33:28
  So basically convince them to say, look, you know, they need a
• 33:31
  vaccine. It's important.
• 33:33
  We cannot just cure people in this, you know, limited part of
• 33:37
  the of the planet. And so how do we do that?
• 33:41
  And so he basically was able to create this GMP facilities in,
• 33:45
  in those countries where they make their own vaccine.
• 33:48
  And with the support from these companies that provide them the
• 33:51
  technology, at least the knowledge to do it.
• 33:54
  Now they make vaccine in countries that otherwise
• 33:56
  wouldn't, wouldn't be able to provide vaccine to their
• 33:59
  population. So I think this is this.
• 34:01
  To me, it's a very strong example of how ethically we
• 34:09
  should think about distributing technologies and you know.
• 34:15
  How to distribute better these technologies?
• 34:18
  Absolutely. And of course, you know, if we
• 34:20
  think about now the next step, which is in vivo gene therapy,
• 34:24
  you know, the, if, if we create this GMP facility that will make
• 34:28
  vaccine, the same facility theoretically can make the same
• 34:32
  tools to, you know, similar tools to do in vivo gene therapy
• 34:34
  so that the, the technology is already there.
• 34:37
  And, and then we can implement that.
• 34:39
  And you don't need to, to be a bone marrow transplanter to cure
• 34:43
  this patient. You need to be a nurse that
• 34:45
  knows how to do an injection in in in those patients so that you
• 34:50
  can basically correct their mutation.
• 34:53
  All these technologies you're describing, how far are they
• 34:56
  from being really? Well, I mean, I can speak for
• 35:02
  myself and probably it's going to take a long time because I'm
• 35:04
  not supported by companies and I don't have like a lot of
• 35:09
  resources. So I have like 3-4 people are
• 35:12
  fantastic in my laboratory, but it's nothing compared to like,
• 35:15
  you know, 50 or 100 people's working in companies with
• 35:20
  $1,000,000 on their back. So and, and if the company I'm
• 35:25
  going to make this technology available in a few years, I'm
• 35:28
  very happy. And my concern is that they
• 35:31
  really also think strongly how to make this technology that's
• 35:34
  curing a disease that mostly prevalent in in poor countries,
• 35:39
  how to make this technology available to those patients and
• 35:43
  children. Yes, where it's needed the most
• 35:45
  really. So there can be other genetic
• 35:47
  disorders. Also, if the technology is
• 35:50
  cheaper, there could be other genetic disorders that.
• 35:53
  Absolutely. I mean, I think one of the my,
• 35:55
  my goal is, I mean, I've been working on hemoglobinopathies
• 36:00
  because I, I knew about it. I come from Italy and it's a
• 36:05
  country that still has a lot of patient with Palestinian sickle
• 36:08
  cell anemia. But one of the thing that I
• 36:11
  focus and now we're talking about sickle cell anemia.
• 36:14
  But in my laboratory, we are at least 5-6 programs to treat
• 36:19
  order and methodological disorders are considered very
• 36:22
  rare because I don't think company as right now they're
• 36:27
  interested, you know, if we're talking about a few 100 patients
• 36:32
  even less. It's difficult to make a lot of
• 36:36
  money. But for me providing tools that
• 36:40
  can help these patients, especially children.
• 36:43
  I work in a pediatric hospital. And if we get to the point that
• 36:47
  they're available, there must be a one point a conversation how
• 36:51
  we support these trials at the academic level, right?
• 36:56
  So if we don't want to do this through a company which may not
• 37:01
  be interested, how do we support, you know, the treatment
• 37:06
  of, you know, I'm at technology can be used by another hospital.
• 37:09
  We can we can transfer that. As you know, as long as they
• 37:13
  don't make a profit, right? It's not they don't act like a
• 37:15
  company. This can be done.
• 37:17
  This can be distributed to different centers.
• 37:19
  So if we have a few patients here, a few patients in another
• 37:22
  country, we can, we can share this information and and the the
• 37:26
  true also from other institution, right?
• 37:29
  They can, we have already a product to to help this group of
• 37:32
  patients. We don't have to restudy,
• 37:35
  reinvent the wheel. We can help you to do treat your
• 37:39
  patient in your country. And the same time with my
• 37:41
  technology potentially we can treat those patients in those
• 37:44
  countries. So if we distribute this
• 37:47
  technology at academic level with some support to do these
• 37:51
  trials, maybe we can convince your, the insurance, you know,
• 37:57
  to help this patient no matter what, because nobody else would
• 38:00
  would do it, right. And maybe in Europe to have and
• 38:03
  and the cost would be lower, you know, because doing this
• 38:05
  academic setting. This is happening with car T
• 38:08
  therapies, yeah, that's the the ones that are academically
• 38:11
  produced. Obviously the prices are cheaper
• 38:15
  and exactly. So there's some kind of proof of
• 38:19
  of concept that this is possible from academia, right of?
• 38:24
  Course, you know, the hospitals in academia, they need a list
• 38:28
  not to lose money, right? I mean, because otherwise it's
• 38:31
  going to be impossible, but, but, but at least to have some
• 38:37
  support to do it right. And and you know, we need to
• 38:40
  define what is really the minimal amount of money required
• 38:43
  to do that. And and of course, you know,
• 38:46
  technology is evolving to a point where now the cost may be
• 38:49
  10 and tomorrow's 9 and hopefully in a few years it's
• 38:52
  going to be 5 and etcetera, etcetera, right.
• 38:54
  And so, but I think we need to start having this conversation.
• 38:59
  How can we reimburse the academic institution to cure
• 39:04
  patient that otherwise would not be cured well?
• 39:07
  Thank you very much, Doctor Vela, for this insightful
• 39:12
  conversation, for sharing all these valuable expertise with
• 39:16
  us. Thank you to all of you for
• 39:19
  listening. And if you'd like this episode,
• 39:21
  please share it with your colleagues and stay tuned for
• 39:24
  our next episodes. Thank you very much.
• 39:27
  Thank you.