Penn sci­en­tists cor­rect ge­net­ic flaw in mice fe­tus­es, ex­pand­ing in utero CRISPR reach to lung dis­eases

Re­mem­ber when re­searchers ap­plied CRISPR to ed­it genes of mice fe­tus­es while they are still in the womb, spar­ing them from death by liv­er dis­ease? The same team from the Uni­ver­si­ty of Penn­syl­va­nia has now test­ed the same idea — al­beit with a dif­fer­ent tech­nique — in ge­net­ic lung dis­eases.

In the bur­geon­ing world of gene edit­ing spawned by CRISPR, in utero treat­ment can be seen as a mid­point be­tween ear­ly em­bryo edit­ing (which pass­es the ge­net­ic al­ter­ations to fu­ture gen­er­a­tions) and edit­ing af­ter birth, which can be too late for pa­tients with cer­tain lethal dis­eases.

William Per­an­teau

It is one of these con­di­tions that study co-lead­ers Ed­ward Mor­risey and William Per­an­teau set out to thwart in their lat­est proof-of-con­cept study, pub­lished in Sci­ence Trans­la­tion­al Med­i­cine this week. Specif­i­cal­ly, they look at a gene tied to sur­fac­tants, a cru­cial lipopro­tein that re­duces lung sur­face ten­sion and en­ables nor­mal lung func­tion. An SFT­PC mu­ta­tion in hu­mans, as in mice, means new­borns are al­most cer­tain to die with­in hours of birth — and that’s what hap­pened with all of the mice in the ex­per­i­ment that were born with the mu­ta­tion.

The team, how­ev­er, man­aged to in­ac­ti­vate the mu­tant gene in some of the fe­tus­es, al­low­ing 7 (out of 87 treat­ed with CRISPR) to sur­vive be­yond 24 hours, in­clud­ing 5 that seemed to re­main healthy for sev­en days.

To specif­i­cal­ly de­liv­er the gene edit­ing reagent to the lungs, the sci­en­tists in­ject­ed it in am­ni­ot­ic flu­id so that with every in­hala­tion, CRISPR would get straight to the ep­ithe­lial cells lin­ing the air­ways. The in­jec­tion took place four days be­fore birth, the equiv­a­lent of hu­mans’ third trimester.

They note that this method re­sult­ed in “rel­a­tive­ly uni­form tar­get­ing of most of the ma­jor pul­monary ep­ithe­lial cell types,” a po­ten­tial ad­van­tage over post­na­tal in­hala­tions that tend to cause dif­fer­en­tial dis­tri­b­u­tion.

“Giv­en that many con­gen­i­tal lung dis­eases such as cys­tic fi­bro­sis and in­her­it­ed [sur­fac­tant pro­tein] dis­ease are gen­er­al­ly caused by mono­genic mu­ta­tions, they should be ide­al can­di­dates for gene edit­ing tech­nolo­gies,” the study au­thors write.

Ed­ward Mor­risey

Like any mouse study, of course, the re­sults are mere­ly signs that re­searchers could pro­ceed with cau­tion. And the re­searchers add that pre­na­tal gene edit­ing can ex­pose the moth­er to risks — some­thing they wouldn’t have to wor­ry about in post­na­tal edit­ing. But the re­searchers are clear­ly stoked about the po­ten­tial here.

“The abil­i­ty to cure or mit­i­gate a dis­ease via gene edit­ing in mid to late ges­ta­tion be­fore birth and the on­set of ir­re­versible pathol­o­gy is very ex­cit­ing,” Per­an­teau said in a state­ment. “This is par­tic­u­lar­ly true for dis­eases that af­fect the lungs, whose func­tion be­comes dra­mat­i­cal­ly more im­por­tant at the time of birth.”

Con­quer­ing a silent killer: HDV and Eiger Bio­Phar­ma­ceu­ti­cals

Hepatitis delta, also known as hepatitis D, is a liver infection caused by the hepatitis delta virus (HDV) that results in the most severe form of human viral hepatitis for which there is no approved therapy.

HDV is a single-stranded, circular RNA virus that requires the envelope protein (HBsAg) of the hepatitis B virus (HBV) for its own assembly. As a result, hepatitis delta virus (HDV) infection occurs only as a co-infection in individuals infected with HBV. However, HDV/HBV co-infections lead to more serious liver disease than HBV infection alone. HDV is associated with faster progression to liver fibrosis (progressing to cirrhosis in about 80% of individuals in 5-10 years), increased risk of liver cancer, and early decompensated cirrhosis and liver failure.
HDV is the most severe form of viral hepatitis with no approved treatment.
Approved nucleos(t)ide treatments for HBV only suppress HBV DNA, do not appreciably impact HBsAg and have no impact on HDV. Investigational agents in development for HBV target multiple new mechanisms. Aspirations are high, but a functional cure for HBV has not been achieved nor is one anticipated in the forseeable future. Without clearance of HBsAg, anti-HBV investigational treatments are not expected to impact the deadly course of HDV infection anytime soon.

UP­DAT­ED: In a land­mark first glimpse of hu­man da­ta from Ver­tex, CRISPR/Cas9 gene ther­a­py sig­nals ear­ly ben­e­fit

Preliminary data on two patients with blood disorders that have been administered with Vertex and partner CRISPR Therapeutics’ gene-editing therapy suggest the technology is safe and effective, marking the first instance of the benefit of the use of CRISPR/Cas9 technology in humans suffering from disease.

Patients in these phase I/II studies give up peripheral blood from which hematopoietic stem and progenitor cells are isolated. The cells are tinkered with using CRISPR/Cas9 technology, and the edited cells — CTX001 — are infused back into the patient via a stem cell transplant. The objective of CTX001 is to fix the errant hemoglobin gene in patents with two blood disorders: beta-thalassemia and sickle cell disease, by unleashing the production of fetal hemoglobin.

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UP­DAT­ED: Make that 2 ap­proved RNAi drugs at Al­ny­lam af­ter the FDA of­fers a speedy OK on ul­tra-rare dis­ease drug

Seventeen years into the game, Alnylam’s pivot into commercial operations is picking up speed.
The bellwether biotech $ALNY has nabbed their second FDA OK for an RNAi drug, this time for givosiran, the only therapy now approved for acute hepatic porphyria. This second approval came months ahead of the February deadline — even after winning priority review following their ‘breakthrough’ title earlier.
AHP is an extremely rare disease, with some 3,000 patients in Europe and the US, not all diagnosed, and analysts have projected peak revenue of $600 million to $700 million a year. The drug will be sold as Givlaari.

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David Ricks. Eli Lilly

Eli Lil­ly touts $400M man­u­fac­tur­ing ex­pan­sion, 100 new jobs to much fan­fare in In­di­anapo­lis — even though it's been chop­ping staff

Eli Lilly is pouring in $400 million to beef up manufacturing facilities at its home base of Indianapolis. The investment, which was lauded by the city’s mayor, is expected to create 100 new jobs.

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Am­gen chops 172 more staffers in R&D, op­er­a­tions and sales amid neu­ro­science ex­it, rev­enue down­turn

Neuroscience wasn’t the only unit that’s being hit by a reorganization underway at Amgen. As well as axing 149 employees in its Cambridge office, the company has disclosed that 172 others nationwide, including some from its Thousand Oaks, CA headquarters, are being let go.

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Stephen Hahn (via Senate HELP Committee)

Stephen Hahn gets through Sen­ate’s soft­ball job in­ter­view — but most­ly plays dodge­ball on the is­sues fac­ing the FDA

Anyone looking for fresh insights on what kind of FDA commissioner Stephen Hahn will be got precious few clues during Wednesday’s Senate hearing on the nomination.

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Op­di­vo/Yer­voy com­bo for melanoma fails in key pa­tient pop­u­la­tion

Bristol-Myers Squibb’s efforts to expand their checkpoint inhibitor combination have run into another recalcitrant cancer.

The NJ-based pharma announced that a combination of Yervoy and Opdivo didn’t beat out Opdivo alone in patients with resected high-risk melanoma who had very low levels of PD-L1. The drug combo couldn’t improve recurrence-free survival in these post-surgery patients.

Ver­tex's stel­lar quar­ter car­ries on with French re­im­burse­ment deal

Vertex’s golden quarter just got brighter. About a month after the US drugmaker finally clinched a deal with UK authorities to cover its slate of cystic fibrosis (CF) drugs following years of protracted negotiations, the company on Wednesday secured a deal with France for its CF therapy, Orkambi.

After the UK, France has one of the largest CF populations outside the United States. Achieving French reimbursement unlocks an ~7000-patient CF population, around ~2500-3000 of which will likely be eligible to receive (and be reimbursed for) Orkambi, Stifel’s Paul Matteis wrote in a note.

Nello Mainolfi, Kymera via Youtube

Kymera hands the helm to No­var­tis vet — and found­ing CSO — Nel­lo Main­olfi

Kymera Therapeutics is turning to a co-founder to run the company.
The protein degradation specialist with a deep-pocket syndicate behind them has opted to give the helm officially to Nello Mainolfi. The new CEO is a veteran of the Novartis Institutes for Biomedical Research. He joined Atlas Venture in their entrepreneur-in-residence program and helped launch Kymera as the CSO three years ago with Atlas’ Bruce Booth.
The boast at Kymera is that they’re angling to create a new class of protein degraders, a popular field where there’s been a variety of startups. One of its chief advocates is NIBR head Jay Bradner, who launched C4 just ahead of joining Novartis, where he’s also been doing new work in the field.