By Meg Tirrell, CNN
(CNN) — Before Johnny Lubin got a potentially life-changing experimental treatment at the age of 13, he recalls, he had one main concern.
“I was worrying that I might get, like, superpowers,” said Johnny, now 15, who lives in Trumbull, Connecticut, about 60 miles north of New York City.
One of an estimated 100,000 people in the US with sickle cell disease, Johnny was also one of the first in the world to try a new kind of medicine: one that uses a gene-editing tool called CRISPR to offer a potential cure.
That treatment, known as exa-cel and made by Vertex Pharmaceuticals and Crispr Therapeutics, is expected to be approved by the US Food and Drug Administration today.
For many in the sickle cell community, it’s been a long time coming. The disease predominantly affects African Americans, afflicting an estimated 1 of every 365 Black babies born, according to the US Centers for Disease Control and Prevention, and has long been considered neglected by the pharmaceutical industry. About 20,000 people in the US are thought to have a severe enough form of the disease to potentially qualify for a treatment like this.
The first ‘molecular disease’
The underpinnings of sickle cell have been understood for almost three-quarters of a century; in 1949, chemist Linus Pauling published a paper in the journal Science describing how the oxygen-carrying protein hemoglobin is different in people with sickle cell, declaring the malady the first “molecular disease.” That was four years before the famous double-helical structure of DNA was proposed.
“We’ve kind of been waiting for this ever since DNA was first discovered,” said Dr. Lewis Hsu, chief medical officer for the Sickle Cell Disease Association of America and a physician who treats kids with sickle cell. “It’s been a long, long time coming.”
Sickle cell is caused by a genetic mutation that leads red blood cells, which contain hemoglobin and ferry oxygen around the body, to be misshapen, like crescents or sickles. These misshapen cells can get stuck in vessels, causing organ damage and – a hallmark of sickle cell – horrible bouts of pain that can last days, called pain crises.
“It was kind of hard for me to do things like have fun and stuff, because I’d always have to be worried about if I’d have a pain crisis,” Johnny said. The pain “would mostly be in my lower back, and it would always be like a pounding pain. … It hurt a lot.”
Until now, the only hope for a cure for people with sickle cell was with a bone marrow, or stem cell, transplant. But Johnny, like more than 80% of patients with sickle cell, couldn’t find a donor that matched.
For the first 13 years of his life, Johnny was hospitalized every few months because of pain crises and other complications from the disease. His parents had to stock opioid pain medicines and always had a “go bag” with them in case they needed to go to the hospital on short notice.
But since October 2021, when Johnny received a one-time infusion of his own gene-edited cells, he hasn’t had another crisis.
“He’s been like a normal child,” said Johnny’s mother, Fabienne Desir. “It’s life-changing for us.”
A new tool for editing genes
CRISPR is a gene editing technique that enables scientists to make precise cuts in DNA. The first scientific paper about it was published in 2012, and its development – by Jennifer Doudna and Emmanuelle Charpentier – won the Nobel Prize in chemistry just eight years later.
For sickle cell, patients’ cells are removed from the body and CRISPR is used to make an edit that turns back on production of fetal hemoglobin, a form of the protein that babies make in the womb. Once the edited cells are returned, the fetal hemoglobin can make up for the mutated hemoglobin that causes sickle cell, explained Dr. Monica Bhatia, chief of pediatric stem cell transplantation at NewYork-Presbyterian/Columbia University Irving Medical Center, who helped run the trial Johnny participated in.
“Fetal hemoglobin, we know, has a higher oxygen-carrying capacity than adult hemoglobin or sickle hemoglobin,” Bhatia said.
Making fetal hemoglobin along with sickle hemoglobin renders a patient similar to someone with sickle cell trait, Bhatia explained; that’s when someone inherits one sickle cell gene and one normal gene, and they “do not have any of the complications of the disease,” she said. “It is more than good enough.”
Indeed, Dr. David Altshuler, chief scientific officer at drugmaker Vertex, pointed out that some people naturally have genetic mutations that keep fetal hemoglobin high, “and they don’t have symptoms, even if they have the disease.”
“So it was like a physiologic, demonstrated approach that would work if you could turn on fetal [hemoglobin],” he said.
Clinical trial results, including Johnny’s, bear that out. In data cited by the FDA ahead of an advisory committee meeting on the therapy in October, 29 of 30 patients reached the trial’s main goal: freedom from a pain crisis for at least 12 months after treatment. The longest time without a crisis was 45.5 months, almost four years, and researchers will continue to follow the patients.
The hope is that the effects could last their entire lives.
“We don’t have as much long-term data as we do for stem cell transplant,” Bhatia said. “But that would be the hope, is that this would be comparable to a transplant and it would be sustained.”
The CRISPR treatment, which is called Casgevy in other countries where it’s already been approved, isn’t the only one on the near-term horizon for sickle cell; another, using a different technology, is only weeks behind, with a potential approval by December 20.
Made by bluebird bio, the second approach involves an older technology, using a virus to deliver a healthy copy of the gene that produces adult hemoglobin to make up for the one producing the sickled form. It also involves removing the patient’s cells from their body, and then returning them. It’s shown similarly encouraging results.
“These both bring tremendous benefit to the patients,” bluebird CEO Andrew Obenshain said.
A million-dollar-plus price tag
Whether people will be able to afford and access these treatments, though, is a key question. One-time genetic treatments typically carry price tags of upwards of $1 million each and require the infrastructure of large medical systems.
“I don’t know whether it will get covered and paid for,” Hsu said. And the types of academic medical centers that could offer the treatment are typically in larger cities, he noted.
“I’m in Illinois, and they’re basically concentrated in Chicago, which leaves the entire rest of the state kind of bare, and so people would have to travel a very long distance to be able to get to this,” he said. “And then some states, there just isn’t anything.”
And the treatment isn’t simple; it requires a lot of additional care around it that adds to the cost. Patients typically stay in the hospital for about a month to prepare for the re-infusion of gene-edited cells, first going through what’s known as “conditioning”: several days of chemotherapy to wipe out their bone marrow, which makes blood cells and platelets, so they’re ready to receive the new cells.
Then, “it takes a period of time for those cells to kind of take up residence in the bone marrow and grow,” Bhatia said.
That period around the infusion can be very difficult for patients and their families; Johnny’s mom described how Johnny’s “whole GI tract was inflamed; he couldn’t swallow. That was really painful. It was hard to watch.”
And that chemotherapy conditioning carries risks, including the possibility of infertility, Hsu noted. He pointed out there are methods of trying to preserve fertility before the treatment, but coverage for that can vary by state as well. And more than half of people with sickle cell in the US depend on Medicaid for their primary insurance, according to the advocacy organization Sick Cells.
The conditioning treatment also carries a potential risk of cancer; two patients in earlier stages of bluebird’s trial died after developing leukemia, which was found unlikely to be related to the gene therapy itself but potentially from the chemotherapy needed to prepare for it.
Vertex’s Altshuler said his company is working on improving the conditioning process to make it gentler, to “create the opportunity for the new cells to go in without any other damage to the body,” although he noted that it’s still in the research phase.
Scientists also are vigilant about potential off-target effects of the CRISPR gene-editing approach – meaning DNA could be cut in an unintended place – and the FDA convened a full-day meeting in October to assess those risks. Many experts there expressed confidence that those risks were “relatively small.”
To Altshuler, the bigger deal in a potential approval of exa-cel is that there’s such an advancement for sickle cell disease, not that it’s the first CRISPR therapy.
“We’re not about a tool; we’re about the disease,” Altshuler said. “Once we found the way in, and now we’ve shown you can treat this disease very effectively if you can increase fetal [hemoglobin], we’re going to drive on that.”
The company is in the very early stages of researching how to achieve an increase in fetal hemoglobin using a pill, so patients wouldn’t need to go through the conditioning and gene editing process, Altshuler said.
He noted that it’s very early days but said that kind of approach could be the answer to the “very valid” question of “how are we going to help people around the world with this therapy?”
The majority of patients with sickle cell live in Africa and India, and bluebird’s Obenshain said the company doesn’t have plans to introduce “this version” of its gene therapy there, noting that it’s too expensive to manufacture.
“Basically, for every patient, we manufacture one drug lot,” Obenshain said.
For Johnny and his family, the effects of his treatment have been so transformative they now celebrate the day he got the infusion of gene-edited cells as his second birthday. He can go swimming – previously an activity guaranteed to trigger a pain crisis – without fear and spent all of last summer in the pool, his family says.
And although he didn’t gain the superpowers he worried about, he got something potentially even better: the chance to be a normal kid.
“I’m starting to teach him how to drive,” said Johnny’s dad, JR Lubin. “So we’re stepping into the regular worry of, you know, raising a teenager.”
& © 2023 Cable News Network, Inc., a Warner Bros. Discovery Company. All rights reserved.
"Meg Tyrrell, CNN: ""Kabla ya Johnny Lubin kupata matibabu ya majaribio ya uwezekano wa kubadilisha maisha akiwa na umri wa miaka 13, alikuwa na wasiwasi mmoja kuu." "Nilikuwa na wasiwasi kwamba ningeweza kupata, kama, nguvu kubwa", alisema Johnny, sasa 15, ambaye anaishi katika Trumbull, Connecticut, karibu maili 100 kaskazini mwa New York City. "Mmoja wa watu 100,000 nchini Marekani walio na ugonjwa wa seli za mviringo, Johnny alikuwa mmoja wa watu wa kwanza duniani kujaribu aina mpya ya dawa: moja ambayo hutumia chombo cha kuhariri jeni kinachoitwa CRISPR kutoa tiba ya uwezekano. """ Dawa hiyo, inayojulikana kama Exacel na iliyotengenezwa na Vertex Pharmaceuticals na Crispr Therapeutics, inatarajiwa kuidhinishwa na Idara ya Chakula na Dawa ya Marekani leo. Kwa wengi katika jamii ya seli za sickle, imekuwa muda mrefu kuja. Ugonjwa huo unawaathiri hasa Waafrika wa Amerika, unaathiri takriban mtoto mmoja kati ya watoto 365 weusi wanaozaliwa, kulingana na Kituo cha Marekani cha Kudhibiti na Kuzuia Magonjwa, na kwa muda mrefu umekuwa ukionwa kuwa umepuuzwa na sekta ya dawa. Watu 20,000 nchini Marekani wana ugonjwa wa ugonjwa wa kisukari ambao unaweza kuhalalisha matibabu ya aina hii. "Mchanganyiko wa molekuli za seli za mviringo unajulikana kama ""seli za mviringo,"" na katika mwaka wa 1949 mtaalamu wa kemia Linus Pauling alichapisha makala katika jarida la Sayansi, akielezea jinsi protini ya hemoglobini inayobeba oksijeni inavyotofautiana kwa watu wenye seli za mviringo, na kutangaza ugonjwa huo kuwa ""seli ya molekuli.""" "Tumekuwa tukisubiri hii tangu DNA ilipogunduliwa kwa mara ya kwanza", alisema Daktari Lewis Hsu, afisa mkuu wa matibabu wa Chama cha Magonjwa ya Sickle Cell cha Amerika na daktari ambaye hutibu watoto wenye ugonjwa wa sickle cell. Sickle cell ni ugonjwa wa chembe za urithi zinazosababisha chembe nyekundu za damu, ambazo zina hemoglobini na kusafirisha oksijeni kuzunguka mwili, kuwa na umbo baya, kama nusu mwezi au nyoka. Chembe hizi zisizo na umbo zinaweza kukwama katika mishipa, na kusababisha uharibifu wa viungo na - sifa ya chembe za sickle - maumivu mabaya ambayo yanaweza kudumu kwa siku nyingi, yanayoitwa matatizo ya maumivu. "Ilikuwa vigumu kwangu kufanya mambo kama vile kujifurahisha na vitu vingine, kwa sababu sikuzote ningehitaji kuwa na wasiwasi ikiwa ningekuwa na mgogoro wa maumivu", Johnny alisema. Maumivu <unk> yangekuwa hasa katika sehemu ya chini ya mgongo wangu, na sikuzote yangekuwa kama maumivu makali. ... Iliniumiza sana. <unk> Hadi sasa, matumaini pekee ya kupata tiba kwa watu wenye ugonjwa wa seli za msalaba yalikuwa kwa kupandikiza uti wa mgongo, au chembe za msingi. Lakini kama asilimia 80 ya wagonjwa wa ugonjwa wa seli za mviringo, Johnny hakuweza kupata mtoaji anayepaswa. Katika miaka 13 ya kwanza ya maisha yake, Johnny alilazwa hospitalini kila baada ya miezi michache kwa sababu ya maumivu makali na matatizo mengine ya ugonjwa huo. Wazazi wake walilazimika kuweka dawa za maumivu ya opioid na daima walikuwa na "mkoba wa kwenda" nao iwapo wangehitaji kwenda hospitalini kwa taarifa fupi. Lakini tangu Oktoba 2021, wakati Johnny alipopokea infusion ya mara moja ya seli zake mwenyewe zilizohaririwa, hajawahi kuwa na mgogoro mwingine. "Amekuwa kama mtoto wa kawaida", alisema mama ya Johnny, Fabienne Desir. "Kuna utafiti unaoonyesha kwamba ""kiwango cha juu cha mabadiliko ya chembe za urithi"" (CRISPR) ni mbinu ya kuchapisha chembe za urithi ambayo inawezesha wanasayansi kufanya vipande vya DNA kwa usahihi." Maandishi ya kwanza ya kisayansi juu ya hii yalichapishwa mnamo 2012, na maendeleo yake - na Jennifer Doudna na Emmanuelle Charpentier - alishinda Tuzo ya Nobel katika kemia miaka minane tu baadaye. Kwa ajili ya seli ya sickle, seli za mgonjwa huondolewa kutoka kwa mwili na CRISPR hutumiwa kufanya uhariri ambao unarudi kwenye uzalishaji wa hemoglobini ya kiinitete, aina ya protini ambayo watoto hufanya katika tumbo la mama. "Kama chembe zilizobadilishwa zinarudi, hemoglobini ya kiinitete inaweza kubadilisha hemoglobini iliyobadilika ambayo husababisha seli ya sickle, ""alieleza Daktari Monica Bhatia, mkuu wa upandikizaji wa seli za msingi za watoto katika Kituo cha Matibabu cha New York-Presbyterian-Columbia University Irving, ambaye alisaidia kuendesha jaribio hilo." "Hemoglobini ya kiinitete, tunajua, ina uwezo mkubwa wa kubeba oksijeni kuliko hemoglobini ya mtu mzima au hemoglobini ya sickle", alisema Bhatia. Kufanya hemoglobini ya kiinitete pamoja na hemoglobini ya sickle hufanya mgonjwa awe sawa na mtu mwenye tabia ya seli ya sickle, Bhatia alielezea; hiyo ni wakati mtu anarithi jeni moja la seli ya sickle na jeni moja ya kawaida, na hawana matatizo yoyote ya ugonjwa huo, "alisema. "Hii ni zaidi ya kutosha. ""Kwa kweli, Daktari David Altshuler, afisa mkuu wa kisayansi katika Vertex, alisema kwamba baadhi ya watu kwa asili kuwa na mabadiliko ya maumbile ambayo kuweka fetal hemoglobin juu, na hawana dalili, hata kama wana ugonjwa. ""Kwa hiyo ilikuwa kama physiological, alionyesha mbinu ambayo ingekuwa kazi kama unaweza kurejea juu ya fetal [hemoglobin],"" alisema." Matokeo ya majaribio ya kliniki, kutia ndani yale ya Johnny, yanathibitisha jambo hilo. Kulingana na takwimu zilizotolewa na FDA kabla ya mkutano wa kamati ya ushauri juu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu ya matibabu. Wakati mrefu zaidi bila mgogoro ulikuwa miezi 45.5, karibu miaka minne, na watafiti wataendelea kufuata wagonjwa. Tumaini ni kwamba athari hizo zinaweza kudumu maisha yao yote. "Hatuna data nyingi za muda mrefu kama tunavyofanya kwa upandikizaji wa seli za shina", Bhatia alisema. "Uchunguzi wa CRISPR, unaoitwa ""Casgill"" katika nchi nyingine ambapo tayari umekubaliwa, sio pekee katika upeo wa muda mfupi kwa seli ya sickle; nyingine, kwa kutumia teknolojia tofauti, ni wiki tu nyuma, na idhini ya uwezekano ifikapo Desemba 20." "Bila shaka, mbinu ya pili inahusisha teknolojia ya zamani, kwa kutumia virusi kutoa nakala ya afya ya jeni ambayo inazalisha hemoglobini ya watu wazima ili kukamilisha moja ya ""sickle"" fomu." Pia inahusisha kuondoa chembe za mgonjwa kutoka kwenye mwili wao, na kisha kuzirudisha. Ni <unk> inaonyeshwa matokeo sawa kuhamasisha. "Hizi zote mbili huleta faida kubwa kwa wagonjwa", alisema Mkurugenzi Mtendaji wa bluebird Andrew Obenshain. "Kwa sababu ya gharama ya dola milioni moja, ""watu wanaweza kununua na kupata matibabu haya, ingawa, ni swali muhimu.""" Matibabu ya mara moja ya maumbile ya kawaida hubeba tags za bei ya juu ya $ 1 milioni kila moja na inahitaji miundombinu ya mifumo mikubwa ya matibabu. "Sijui kama itashughulikiwa na kulipwa", Hsu alisema. Na aina za vituo vya matibabu vya kitaaluma ambavyo vinaweza kutoa matibabu kwa kawaida viko katika miji mikubwa, alibainisha. "Mimi niko Illinois, na wao ni kimsingi umakini katika Chicago, ambayo inaacha nzima mapumziko ya hali aina ya tupu, na hivyo watu itakuwa na kusafiri umbali mrefu sana kuwa na uwezo wa kupata hii", alisema. <unk>Na kisha baadhi ya majimbo, kuna tu <unk> hakuna kitu.<unk> Na matibabu si rahisi; inahitaji mengi ya huduma ya ziada kuzunguka ambayo inaongeza kwa gharama. Kwa kawaida wagonjwa hukaa hospitalini kwa mwezi mmoja ili kujitayarisha kwa ajili ya kuingizwa tena kwa chembe zilizobadilishwa kwa jeni, kwanza kupitia kile kinachojulikana kama "kufanya kazi: siku kadhaa za tiba ya kemikali ili kuondoa uti wa mgongo wa mifupa, ambayo hufanya chembe za damu na platelets, hivyo wako tayari kupokea chembe mpya. Kisha, "inachukua muda kwa chembe hizo kukaa katika uti wa mgongo na kukua", alisema Bhatia. Kipindi hicho karibu na infusion inaweza kuwa ngumu sana kwa wagonjwa na familia zao; Mama ya Johnny alielezea jinsi Johnny's <unk> njia nzima ya tumbo ilikuwa imepatwa na uchochezi; hakuweza kumeza. Hilo lilikuwa jambo lenye kuumiza sana. Ilikuwa vigumu kutazama. <unk> Na kwamba chemotherapy conditioning hubeba hatari, ikiwa ni pamoja na uwezekano wa utasa, Hsu alibainisha. "Amesema kuna njia za kujaribu kuhifadhi uzazi kabla ya matibabu, lakini chanjo kwa ajili ya hilo inaweza kutofautiana na hali pia. """ Zaidi ya nusu ya watu walio na ugonjwa wa Sickle Cell nchini Marekani wanategemea Medicaid kwa bima yao ya msingi, kulingana na shirika la utetezi Sick Cells. Matibabu ya hali ya juu pia hubeba hatari ya saratani; wagonjwa wawili katika hatua za mapema za jaribio la bluebird walikufa baada ya kuendeleza leukemia, ambayo iligunduliwa kuwa haiwezekani kuhusiana na tiba ya jeni yenyewe lakini uwezekano kutoka kwa kemotherapy inayohitajika kuitayarisha. Altshuler alisema kampuni yake inafanya kazi ya kuboresha mchakato wa hali ya hewa ili kuifanya iwe laini zaidi, ili "kuunda fursa ya seli mpya kuingia bila uharibifu mwingine wowote kwa mwili", ingawa alibainisha kuwa bado iko katika awamu ya utafiti. Wanasayansi pia wana tahadhari juu ya athari za uwezekano wa nje ya lengo la mbinu ya uhariri wa jeni ya CRISPR - ikimaanisha DNA inaweza kukatwa mahali ambapo haikutarajiwa - na FDA ilikusanya mkutano wa siku nzima mnamo Oktoba kutathmini hatari hizo. Wataalamu wengi huko walionyesha ujasiri kwamba hatari hizo zilikuwa ndogo kwa Altshuler, mpango mkubwa katika idhini ya uwezekano wa exa-cell ni kwamba kuna maendeleo kama hayo kwa ugonjwa wa seli ya sickle, sio kwamba ni tiba ya kwanza ya CRISPR. "Hatujui kuhusu chombo; tunajua kuhusu ugonjwa", alisema Altshuler. "Kama tumeona njia ya kuingia, na sasa tumeonyesha unaweza kutibu ugonjwa huu kwa ufanisi sana kama unaweza kuongeza [hemoglobini] ya kiinitete, tutaendesha juu ya hilo. ""Kampuni iko katika hatua za mapema sana za kutafiti jinsi ya kufikia ongezeko la hemoglobini ya kiinitete kwa kutumia kidonge, kwa hivyo wagonjwa hawatahitaji kupitia mchakato wa hali na uhariri wa jeni, "Altshuler alisema." "Amesema kuwa ""ni siku za mapema sana, lakini aina hiyo ya mbinu inaweza kuwa jibu kwa swali la ""halali sana"" la ""je tutaweza kuwasaidia watu ulimwenguni kote na tiba hii?"" ""Watu wengi wenye ugonjwa wa seli za sickle wanaishi Afrika na India, na Obenshain wa Bluebird alisema kampuni hiyo haina mipango ya kuanzisha toleo hili la tiba ya jeni huko, akisema ni ghali sana kutengeneza." "Kimsingi, kwa kila mgonjwa, tunatengeneza dawa moja", Obenshain alisema. Kwa Johnny na familia yake, athari za matibabu yake zimekuwa za kubadilisha sana hivi kwamba sasa wanasherehekea siku alipopata infusion ya seli zilizobadilishwa jeni kama siku yake ya kuzaliwa ya pili. Anaweza kwenda kuogelea - hapo awali shughuli iliyohakikishwa kuamsha mgogoro wa maumivu - bila hofu na alitumia majira yote ya joto iliyopita katika dimbwi, familia yake inasema. Na ingawa hakupata nguvu kubwa alizokuwa ana wasiwasi nazo, alipata kitu ambacho kilikuwa bora zaidi: nafasi ya kuwa mtoto wa kawaida. "Ninaanza kumfundisha jinsi ya kuendesha gari", akasema baba ya Johnny, JR Lubin. "Kwa hivyo tunaingia katika wasiwasi wa kawaida wa, unajua, kulea kijana. "" & © 2023 Cable News Network, Inc., a Warner Bros. Kampuni ya Ugunduzi. Haki zote zimehifadhiwa.